Receptor

cell signaling

2010-12-31T23:58:00.000-08:00

Cells, whether unicellular organisms or cells within multicellular organisms, adjust to signals within their environment and communicate with other cells.

▼ autocrine : cellular responses : combinatorial : contact-dependent signaling : cytokines : delay/rapidity : distance of signal : endocrine : environmental signals : evolution : histidine kinase : hormones : neuronal signaling : neurotransmitters : paracrine : prokaryote signaling : rapidity/delay : receptor proteins : receptors : regulator proteins : SH domains : signal termination : signaling distance : signal transduction ▼

Receptors are molecules that receive signals by binding ligands, for which receptors have varying binding affinity. Signal transduction is the process of converting signals from one form to another, ultimately adjusting an intracellular process, as in metabolic regulation, or an intranuclear process, such as gene expression.

Signaling operates at various distances:
● contact signaling – particularly important in immune signaling and during development

signaling mediated by synthesized signal mediators
● autocrine – chemical mediators (cytokines, growth factors) that operate on the cell that produces the mediator [1, 2]

signaling mediated by secreted signal mediators
● paracrine – short-range
● endocrine – long-range via hormones

Neurons signal at long-range by virtue of their long axonal processes, but neurotransmitters released into the synaptic cleft operate at short-range, enabling rapid, precise signaling.

Speed of signaling is determined by:
● speed of production of the signal (synthesis of mediators)
● speed of delivery of signal mediators (delivery of mediators to target cells)
● speed of cellular response to the signal
● depolarization, impulse propagation, repolarization of nerve cells

Signals are terminated by:
● dissociation of mediator ligand from receptor
● absorption of mediator by neighboring target cells (neurotransmitters and other paracrine mediators)
● enzymatic destruction of mediators
● immobilization by adsorption of mediators in ECM or by binding to intracellular proteins

Signal transduction is usually performed by enzymes in association with second messengers. Signaling proteins operate in a combinatorial fashion within signaling networks, greatly extending the biological roles of individual proteins. The simplest such system comprises two components – a histidine kinase protein that receives a signal and transmits it, via phosphorelay, to a partner response-regulator protein. Protein domains and motif interactions display considerable flexibility, providing an obvious evolutionary advantage. For example, single amino acid substitutions alter the binding specificity of SH2 domains such that specificity can change quite rapidly, enabling formation of new signaling connections as metazoan organisms became more complex.

Environmental signals include mechanical stimuli (light, sound) and chemical stimuli. The origin of a biochemical stimulus may be the cell itself (autocrine), adjacent cells (paracrine), the plasma membrane of adjacent cells (contact inhibition), or distant cells (endocrine).

Neurotransmission incorporates interaction between neurotransmitters and specific receptor proteins. Cytokines mediate paracrine stimulation, and hormones mediate endocrine stimulation.

Cellular responses to signaling include:
● alterations in gene expression (transcription)
● alteration of electrophysiological charge
● cellular cycling and reproduction
● regulation of cellular metabolic processes
● biosynthesis with or without secretion
● cellular growth
● chemotaxis, migration, and, in multicellular organisms, extravasation
● initiation of immune and inflammatory responses
● differentiation into cell lines or maturation of cell lines
● cellular survival or apoptosis

Intracellular interactions in prokaryotes
Four kinds of cell interactions can be distinguished:
1) Transfer of a chemical signal from one cell to another. The variety of such transfers is presented in several examples.
2) Signaling by direct physical contact between two cell bodies, which may involve their surfaces or cell appendages, such as fibrils, pili, or flagella (bacterial flagella). Direct physical contact is often involved in cell swarming.
3) Syntrophic metabolism. Schink Syntrophism Among Prokaryotes.
4) Gene transfer from one cell to another.

• bacterial interactions • concentration gradients • ion channels • protein pumps • receptor proteins • receptor-mediated endocytosis • GPCRs • GPCR families • hormones • neurotransmission • Nitric Oxide • neuronal interconnections • phosphotransfer-mediated signaling pathways • Protein Kinase Signaling Networks • signaling gradients :

KEGG Encyclopedia : Pathway ABC transporters : Pathway Phosphotransferase system (PTS) : Pathway Two-component system : Pathway MAPK signaling pathway : Pathway Wnt signaling pathway : Pathway Notch signaling pathway : Pathway Hedgehog signaling pathway : Pathway TGF-beta signaling pathway : Pathway VEGF signaling pathway : Pathway Jak-STAT signaling pathway : Pathway Calcium signaling pathway : Pathway Phosphatidylinositol signaling system : Pathway mTOR signaling pathway : Pathway Neuroactive ligand-receptor interaction : Pathway Cytokine-cytokine receptor interaction : Pathway ECM-receptor interaction : Pathway Cell adhesion molecules (CAMs) : Orthology Transporters (+diseases) : Orthology Two-component system : Orthology Receptors and channels (+diseases) : Orthology Cytokines :
Orthology Cell adhesion molecules (CAMs) : Orthology CAM ligands : Orthology CD molecules :
Orthology GTP-binding proteins :

cell-surface receptors

2010-12-22T19:12:00.000-08:00

Receptors on cell-surfaces participate in intercellular signaling by transducing conformational change, which is induced in the receptor upon ligand-binding, into intracellular signaling and altered biophysiological activity. Thousands of receptors of varying specificity for activating ligands participate in the fine-tuned network of signaling cascades that is essential for biological functioning.

This bewildering array of receptors is variably classified according to ligand, receptor, or pathway and includes the largest protein family known (GPCRs).

Broadly, surface receptors responsive to hormones are divided into indirect-enzymatic metabotropic receptors and direct-ion channel, ionotropic receptors.

GPCR

2010-12-18T08:46:00.000-08:00

Guanine nucleotide-binding protein-coupled receptors, G-protein coupled receptors, GPCRs, serpentine receptors, 7TM receptors, or heptahelical receptors are a large family of protein receptors in which an intracellular G-protein is coupled to a transmembrane receptor.

▼ alpha-helices : cascade : effector enzymes : evolution : families : functions : GABA receptors : GDP/GTP : G-proteins : inorganic stimuli : opioid receptor : PDZ domains : phylogeny : physical stimuli : second messengers : stimuli : transmembrane receptors : trimeric ▼

GPCRs transduce signals from transmembrane receptors for sensory, hormonal, chemical, or photic stimuli into regulation of effector enzymes and ion channels, chemotaxis, and cellular signal transduction. GPCRs are diverse and of ancient unicellular evolutionary origin, and are found in fungi, plants, and animals. Sequence similarities of 7TM receptors, which stem from phylogenetic relatedness, are confined largely to the transmembrane domains. They share a common structure of plasma membrane-spanning helices with seven hydrophobic domains (7-TMSs). GPCRs are typically 20-28 amino acid residues long.

GPCRs are trimeric proteins that respond to a variety of specific ligands and stimuli – for example, photons, ions, biogenic amines, nucleosides, lipids, amino acids, and peptides. GPCRs are the only non-ion-channel plasma membrane receptors that are activated by inorganic chemicals and physical stimuli. Transmembrane GPCRs bind GDP when inactive, and switch the bound nucleotide to GTP when activated. Although most GPCRs do not require dimerization for their function, some receptors such as the gamma-amino butyric acid (GABA) receptors require heterodimerization of paralogs for their proper expression and function. [r]

The signalling cascade begins with attachment of a specific ligand, signaling molecule, neurotransmitter, cellular adhesion molecule, hormone, steroid, cytokine, or a specific energetic stimulus, which initiates brief (seconds) binding of GTP rather than GDP. Signal transduction is accomplished through the coupling of G-proteins, via second messengers, to various secondary pathways involving ion channels, adenylyl cyclases, and phospholipases. Further, GPCRs may also couple to other proteins, such as those containing PDZ domains. Second messengers include adenosine 3',5'-monophosphate (cAMP), cGMP, phosphoinositides, diacylglycerol (DAG), and calcium ions. Triggered events include activation of kinase cascades and phosphorylation of cytosolic factors and nuclear transcriptional factors. Activated GPCRs also recruit GPCR receptor kinases (GRKs) that phosphorylate the receptors themselves to facilitate termination of signaling or receptor turnover.

GPCR functions include:
a) generation of second messengers including cGMP and IP3, which stimulate phosphorylation reactions, causing release of second-messenger calcium ions from storage in ER,
b) generation of cAMP and activation of the transcription factor, cAMP response element binding protein (CREB) to stimulate gene transcription
c) cellular signal transduction
d) regulation of gene transcription
e) chemotaxis
f) ion channel opening (confromational change) in response to neurotransmitters

: animation G-protein : Tables Second Messengers Cell signaling RTKs :

It is anticipated that future elucidation of GPCR constitution will reveal alpha-helical structures, consisting of 20 to 28 amino acids each.

On-line structural representations for the human µ opioid receptor, for example, is available as a 2D schematic. The 3D structure for inactive (dark) rhodopsin has been established, and the GPCRDB server holds atomic coordinates of 3D models of GPCRs. For more detailed information on-line about GPCRs, consult the GPCR database at GPCRDB.

The GPCRs have been divided into at least six families of GPCRs showing little to no sequence similarity, which can not be traced to a single evolutionary origin.

Tables Cell signaling Receptor Tyrosine Kinases(RTK) :

• CELL SIGNALING ~ ERKs • GPCRs • GPCR families • hormones • Nitric Oxide• neurotransmission • neuronal interconnections ~ PKA, protein kinase A ~ PKC ~ protein kinase A ~ protein kinase C ~ protein tyrosine kinases • phosphotransfer-mediated signaling pathways • Protein Kinase Signaling Networks • receptor tyrosine kinases • Receptor Tyrosine Kinases (RTKs) Cell signaling • signaling gradients • signal transduction • two-component systems • animation MAPK signal transduction : animation G-protein :

Signaling pathways:
Pathway ABC transporters : Pathway Phosphotransferase system (PTS) : Pathway Two-component system : Pathway MAPK signaling pathway : Pathway Wnt signaling pathway : Pathway Notch signaling pathway : Pathway Hedgehog signaling pathway : Pathway TGF-beta signaling pathway : Pathway VEGF signaling pathway : Pathway Jak-STAT signaling pathway : Pathway Calcium signaling pathway : Pathway Phosphatidylinositol signaling system : Pathway mTOR signaling pathway : Pathway Neuroactive ligand-receptor interaction : Pathway Cytokine-cytokine receptor interaction : Pathway ECM-receptor interaction : Pathway Cell adhesion molecules (CAMs) :

hormones

2010-12-17T09:08:00.000-08:00

Hormones are molecules that are excreted by exocrine cells and that act at a site distant from their point of excretion by ligating receptor proteins.

Steroid hormones exert their effects by binding to various specific receptor proteins, forming complexes with transcription factors that bind to response elements of genes. Response elements are sequences of DNA that are located in promoter or enhancer sequences, and which contain short consensus sequences.

Estrogen response element (ERE) – estrogen binds to the estrogen receptor transcription factor; consensus sequence AGGTCANNNTGACCT.

Glucocorticoid response element (GRE) – glucocorticoids bind to the glucocorticoid receptor transcription factor; consensus sequence AGAACANNNTGTTCT

Hormones such as adrenaline, glucagon, luteinizing hormone (LH), parathyroid hormone (PTH), and adrenocorticotropic hormone (ACTH) interact with GPCRs to cause an increase in the cyclic nucleotide, second messenger, cAMP. Atrial natriuretic peptide (ANP) interacts with GPCRs to elevate levels of the cyclic nucleotide, second messenger, cGMP. The the peptide/protein hormones vasopressin, thyroid-stimulating hormone (TSH), and angiotensin, via activate phospholipase C (PLC).

Ca²⁺ ions, which are the most widely employed second messengers, are involved in the secretion of hormones such as insulin.

immune receptors

2010-12-16T11:11:00.000-08:00

The functionality of cells of the immune system is particularly dependent on signal pathways, and the various lymphoid cell types sport an array of receptors.

▼ antigenic determinant : APC costimulation : BCR: complement receptors : cytokines : epitope : FcR : Ig-Fc : IgG : opsonins : pathogen associated molecular patterns : pattern recognition receptors : phagocyte receptors : respiratory burst complement : respiratory burst Fc : : scavenger receptors : TCR : TLR : Toll-like receptors : VDJ recombination ▼

Phagocytes

Phagocytic cells detect infectious agents that bind to a variety of receptors on the phagocytes cell membranes, including:

● Fc receptors (FcR, Ig-Fc) – the constant region (Fc) of IgG on bacterial surfaces can bind to the Fc receptor on phagocytes. Such binding to the Fc receptor requires prior antibody-antigen interaction. The binding of IgG-coated bacteria to phagocytic Fc receptors stimulates both metabolic activity in the phagocytes (respiratory burst) and phagocytic activity. Fc receptors include the clusters of differentiation, CD16 (Fcγ RIII), CD32 (Fcγ RII-A, Fcγ RII-B2, Fcγ RII-B1), and CD64 (Fcγ RI), Fcε RI, and Fcα RI. All FcR are stimulatory except inhibitory Fcγ RII-B1 and B2, which contain immunoreceptor tyrosine based inhibition motifs (ITIMs) in their cytoplasmic tail. Table Fc receptors

● Complement receptors – Phagocytic cells possess a receptor for the C3b complement opsonins, and binding of C3b-coated bacteria to this receptor stimulates enhanced phagocytosis and the respiratory burst. Table Complement Receptors.

● Scavenger receptors bind a variety of polyanions on bacterial surfaces, stimulating phagocytosis of the polyanion-coated bacteria. Macrophage scavenger receptors appear to mediate important, conserved functions, so it was likely pattern-recognition receptors that arose early in the evolution of host-defense mechanisms. Table Scavenger Receptors

● Toll-like receptors are a variety of pattern recognition receptors (PRR) that recognize pathogen associated molecular patterns (PAMP) on infectious agents. Binding of the infectious agents to Toll-like receptors stimulates phagocytosis and the release of inflammatory cytokines (IL-1, TNF-α, IL-6) from the phagocytes. Table Toll-like Receptors

Tables Complement Receptors Fc receptors Immune Cytokines Immunoglobulins Interferons Scavenger Receptors Toll-like Receptors .

Lymphocytes

The surfaces of B cells and T cells are coated with thousands of identical copies of different integral membrane receptors (BCRs, TCRs), each capable of binding with a different antigen.

Receptor characteristics
● thousands of copies of integral membrane proteins with unique antigen binding sites
● encoded by genes assembled by VDJ recombination produced without antigen encounter
● the antigen binding site recognizes an antigenic determinant or epitope on the antigen
● binding, by non-covalent forces, is based on complementarity of the surface of the receptor and the surface of the epitope

Binding of receptor to epitope, when accompanied by APC-costimulation, leads to:
● stimulation of the B or T cell to leave the G0 phase and enter the cell cycle
● repeated mitosis generates a clone of cells of identical specificity, each coated with an identical antigen receptor.

Cytokine receptors:
● Hematopoietin family receptors are dimers or trimers with conserved cysteines in their extracellular domains and a conserved Trp-Ser-X-Trp-Ser sequence. The two subunits are i) cytokine-specific, and ii) signal transducing. Examples are receptors for IL-2 through IL-7 and GM-CSF.
___ ● Colony-stimulating factors (CSFs) are glycoprotein molecules that support growth of hematopoietic colonies. Examples are receptors for interleukin 3 (IL-3), G-CSF, GM-CSF, M-CSF.

● Interferon family receptors
Interferons are immune cytokines that are classified, as type I, II, or III, according to the receptors through which they signal. Interferon (INF) family receptors have conserved cysteine residues and include the receptors for IFNα, IFNβ, and IFNγ.

● Tumor Necrosis Factor family receptors possess four extracellular domains. Examples are receptors for TNFα, TNFβ (lymphotoxin β, LT), CD40, CD27, CD30, and Fas.

● Chemokine family receptors have seven transmembrane helices (serpentine, GRCRs) and interact with G protein. This family includes receptors for IL-8, MIP-1, MCP (monocyte chemoattractant protein), and RANTES (regulated upon activation normal T cell expressed and secreted). Chemokine receptors CCR5 and CXCR4 are used by HIV to preferentially enter either macrophages or T cells.

Tables Complement Receptors Fc receptors Immune Cytokines Immunoglobulins Interferons Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers Scavenger Receptors Toll-like Receptors

▲ф ф antibodies ф antigen : antigenic determinant ф APCs : APC costimulation : BCR ф BCR ф B cells ф CD ф cellular response ф clonal selection ф complement system : complement receptors ф complement system ф costimulation : cytokines ~ cytokines ф dendritic cells : epitope : FcR Fc receptors ф granulocytes ф helper T cell ф hematopoiesis ф humoral immunity : Ig-Fc : IgG Immune Cytokines Immunoglobulins □□ Immunology ~ immunoglobulins ф inflammatory response ф immune cytokines ф immune response ф lymphocytes ф lymphoid system ф macrophages ф MHC : opsonins ф pathogens : pathogen associated molecular patterns (PAMP) : pattern recognition receptors (PRR) ф pattern-recognition receptors : phagocyte receptors ф phagocyte ф plasma cells : respiratory burst complement ››› respiratory burst : respiratory burst Fc : scavenger receptors ф signaling ф surface receptors : TCR ф TCR ф T cells : TLR : Toll-like receptors : VDJ recombination ▲ф

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immune signaling

2010-12-16T11:10:00.000-08:00

In cells of the immune system, signaling leads to activation of cell-type specific immune activities. Ligand interaction with receptors on the surface of cells of the immune system triggers intracellular signal transduction directly or through association with assistant signal transduction molecules (CD3, IgαIgβ, etc.).

Cytokines are secreted by immune cells in response to cellular signaling, and bind to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter cellular activity (gene expression). Interleukins comprise the largest class of cytokines, and are manufactured by one leukocyte to act on other leukocytes as signaling ligands. Cytokines are often produced in cascades.
Cytokine receptors:
● Hematopoietin family receptors
___ ● Colony-stimulating factors (CSFs)
● Interferon family receptors
● Tumor Necrosis Factor family receptors
● Chemokine family receptors

Phagocytic cells of the innate immune response employ:
● Fc receptors (FcR, Ig-Fc)
● Complement receptors
● Scavenger receptors
● Toll-like receptors
__ ● adaptor proteins with TIR domains

Activation of lymphocytes signaling of the adaptive immune response requires:
● lymphocyte receptors, associated with
● ITAM-bearing signal transduction molecules, and
● CD45
● adaptor proteins
● second messengers

Immune signaling serves a variety of functions:
● Pre-peripheral-antigen binding
_ ● apoptotic deletion of cells bearing receptors against self-peptides
● Post-peripheral-antigen binding
_ ● activation of immune and inflammatory response activities
__ ● secretion of immune mediator molecules – acute phase components, antibodies, ingestion, disgestion, externalization, and presentation of fragmented antigen (epitope peptide), complement components, cytokines, eicosanoids (prostaglandins and leukotrienes), kinins
__ ● production of inhibitory molecules, such as IκB that regulate immune activity
__ ● surface expression of cell-type specific markers and receptors
__ ● expression of surface receptors fine-tuned by somatic hypermutation
__ ● activation of clonal expansion by entry into cell cycle and proliferation
__ ● activation of cellular differentiation from precursor to committed cell lines
__ ● activation of cellular maturation from cell line to specialized cells
__ ● cellular survival responses
__ ● chemotaxis, migration, and leukocyte adhesion cascade

Signaling in the innate immune response :

Pattern recognition receptors (PRR) are a class of innate immune response-expressed proteins that respond to pathogen-associated molecular patterns (PAMP) and endogenous stress signals termed danger-associated molecular patterns (DAMP). The evolutionarily more recent adaptive immune response employs diverse surface receptors that display decremental binding affinities for epitope stimuli.

Pattern recognition receptors include:
● Membrane-associated PRR
_____ ● Toll-like receptors (TLR) that sense pathogen-associated or damage-associated molecular patterns. In Drosphila, Toll and immunodeficiency (Imd) receptors may link innate and adaptive immune responses (Fig), responding to bacterial and fungal pathogens and activating NF-κB homologs (Dif, dorsal and Relish), thus driving antimicrobial peptide gene expression.[ffta]
● Cytoplasmic PRR
● Secreted PRR, including complement receptors

Toll-like receptors (TLRs) appear to be one of the most ancient, conserved components of the immune system, and are the basic signaling receptors of the innate immune system. TLRs are activated by molecules associated with pathogens (PAMPs) or with injured host cells/tissue (DAMPs). Most identified TLR ligands are either conserved microbial products that signal the presence of an infection, or endogenous ligands resulting from other danger conditions. TLRs trigger signals evoking synthesis and secretion of cytokines and activation of host defenses through NF-κB, MAP kinases, and costimulatory molecules.

The TLR family is characterized by the presence of leucine-rich repeats, which mediate ligand binding, and co-receptors with the Toll/interleukin-1 receptor-like domain (TIR), which mediate interaction with intracellular signaling proteins. To avoid excessive inflammatory responses, TLR signalling must be tightly regulated. MAPK phosphatase 1 (MKP1) is a key negative regulator of Toll-like receptor (TLR)-induced inflammation in vivo. Phosphorylation of MAPK p38 — which is associated with the modulation of cytokine production — is considerably increased and prolonged in the absence of MKP1. [MKP1]
Table Toll-like Receptors

NF-κBs, Nuclear Factor kappa Bs, are ubiquitous transcription factors involved in responses to cellular stressors such as cytokines, bacterial antigens, and viral antigens. Free NF-κB translocates to the nucleus where it binds to specific κB sequences in DNA, initiating transcription of related genes, including those for immunoreceptors, cytokines, and its own inhibitor, IκB. Inhibitor of kappa B (IκB, IkappaBalpha) inactivates NF-κB by sequestering NF-κB dimers within the cytoplasm. Physiological activities mediated by NF-κB include cellular proliferation, and inflammatory, immune, and cellular survival responses.
[] signaling pathways []

Signaling in the adaptive immune response :

Antigens act as ligands for BCR, while epitope peptide•MHC complexes act as ligands for TCR. Hematopoietic growth factors stimulate cell division in immune and blood cell lines.

Signal transduction molecules:
Because both BCR and TCR have very short cytoplasmic domains, they must associate with invariant signal transduction molecules in order to generate an intracellular signal (IgαIgβ for BCR, CD3 for TCR). The antigen-specific receptors and signal transduction molecules cluster together in the plasma membrane, and signaling is effected by long ITAM-containing cytoplasmic domains on the signal transduction molecules. ITAMs are immunoreceptor tyrosine-based activation motifs that are phosphorylated by src-family protein tyrosine kinase enzymes (PTK). Protein kinases add phosphate groups to tyrosine (or serine or threonine) residues of other proteins, often those of enzymes. Phosphatases remove the phosphate groups, reversing the effects of protein kinases. Phospholipases such as PLC cleave specific ester bonds in phosphoglycerides or glycerophosphatidates, converting the phospholipids into fatty acids and other lipophilic substances. Phospholipase C-γ cleaves the membrane phospholipid, phosphatidylinositol bisphosphate (PIP2) into the signaling molecules, inositol trisphosphate (IP3) and diacylglycerol (DAG).

Phosphorylation can activate or inactivate enzymes, or can create binding sites that lead to increased concentration of cytoplasmic proteins (and hence their accessibilty for phosphorylation). Activation of lymphocytes also requires CD45 (common leukocyte antigen), which is necessory for receptor-mediated activation of lymphocytes.

Phosphorylated ITAMs can bind to other PTKs (Syk for B cells, ZAP-70 for T cells), triggering a cascade of cytoplasmic enzymes or second messengers, such as calcium ions, diacylglycerol, G-proteins, IP3, MAP kinases, PKCs, and transcription factors, such as NF-κB. Ultimately, gene expression via transcription of mRNA leads to immune activities.

Tables Apoptosis vs Necrosis Apoptosis Cell Adhesion Molecules Cell signaling Complement Receptors Cytokines Eicosanoid Actions Fc receptors Immunoglobulins Interferons Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers Scavenger Receptors Toll-like Receptors

intracellular receptors

2010-12-16T10:04:00.000-08:00

While a large number of cell-surface receptors are employed in receiving environmental signals, fine-tuning of intracellular signaling relies upon a larger number of intracellular receptors and 'signaling' enzymes.

Location of intracellular receptors
● nucleus
● endoplasmic reticulum
● cytoplasm
● intracellular vesicles [s]

Families include receptors/for :
● constitutive androstane receptor (CAR, nuclear receptor subfamily 1, group I, member 3, NR1I3)
● farnesoid X receptor (FXR, nuclear receptor subfamily 1, group H, member 4, NR1H4)
● IP3 receptor (inositol triphosphate, IP3, inositol 1,4,5-triphosphate receptor, type 1, ITPR1)
● liver X receptor
● peroxisome proliferator-activated receptors (PPARs, α, γ and δ)
● pregnane X receptor
● retinoic acid receptor (RARA)
● retinoid X receptor (RXRA)
● sigma1 (neurosteroids)
● steroid and sex hormones
● thyroid hormone (α and β)

lymphocyte receptors

2010-12-13T01:11:00.000-08:00

Lymphocytes are coated with surface receptors that participate in the signaling that regulates the adaptive immune response. B lymphocytes carry antibody/ immunoglobulin BCR, while T lymphocytes carry different Ig superfamily TCR.

▼ antigen-MHC complex : BCR : cascade : CD3 : CD4 : CD8 : CD45 : common leukocyte antigen : co-receptor CD4, co-receptor CD8 : cross-linked BCR : enzymes : Fc receptors (FcR) : IgαIgβ : immunoreceptor tyrosine-based activation motifs : intracellular signal : invariant TCR chain : ITAMs : Lck : leukocyte common antigen : lymphocyte receptors : multivalent antigens : phosphorylation : phosphorylated ITAMs : protein kinases : second messengers : signal transduction complex - CD3 : signal transduction molecules : src-family protein tyrosine kinases (PTKs) : Syk : TCR : TCR-CDR3 : TCR diversity : TCR heterodimers : TCR-Ig superfamily : ZAP-70 ▼

Activation of signaling requires
● lymphocyte receptors, associated with
● ITAM-bearing signal transduction molecules, and
● CD45
● adaptor proteins
● second messengers

Signal transduction molecules:
Because both BCR and TCR have very short cytoplasmic domains they must associate with invariant signal transduction molecules in order to generate an intracellular signal (IgαIgβ for BCR, CD3 for TCR). The antigen-specific receptors and signal transduction molecules cluster together in the plasma membrane, and signaling is effected by long ITAM-containing cytoplasmic domains on the signal transduction molecules. ITAMs are immunoreceptor tyrosine-based activation motifs that are phosphorylated by src-family protein tyrosine kinase enzymes (PTK). Protein kinases add phosphate groups to tyrosine (or serine or threonine) residues of other proteins, often those of enzymes. Phosphatases remove the phosphate groups, reversing the effects of protein kinases. Phospholipases such as PLC cleave specific ester bonds in phosphoglycerides or glycerophosphatidates, converting the phospholipids into fatty acids and other lipophilic substances. Phospholipase C-γ cleaves the membrane phospholipid, phosphatidylinositol bisphosphate (PIP2 ) into the signaling molecules, inositol trisphosphate (IP3) and diacylglycerol (DAG).

Phosphorylation can activate or inactivate enzymes, or can create binding sites that lead to increased concentration of cytoplasmic proteins (and hence their accessibilty for phosphorylation). Activation of lymphocytes also requires CD45 (common leukocyte antigen), which is necessory for receptor-mediated activation of lymphocytes.

Phosphorylated ITAMs can bind to other PTKs (Syk for B cells, ZAP-70 for T cells), triggering a cascade of cytoplasmic enzymes or second messengers, such as calcium ions, diacylglycerol, G-proteins, IP3, MAP kinases, PKCs, and transcription factors. Ultimately, gene expression via transcription of mRNA leads to immune activities.

Lymphocyte receptors: BCR and TCR

BCR
Heavy chain (H) plus kappa (κ) or lambda (λ) chains.

The surfaces of B cells are coated with one of thousands of distinct Ig superfamily receptors, diversified through VDJ recombination, which bind to their cognate antigen at their antigen-binding site.

Multivalent antigens can cross-link BCR, generating signals of greater amplitude in B cells, and potentially activating the B cells to proliferate and synthesize IgM in the absence of T cell- costimulation. While B cell activation may be possible without antigen presentation, B cells are more efficiently activated by binding of BCR to an array of identical epitopes that are bound to antibody on the Fc receptors (FcR) of macrophages and neutrophils.

TCR
Alpha (α) and beta (β) or gamma (γ) and delta (δ) chains

As T cells develop in the thymus, TCR gene segments are recombined to generate diverse, unique TCRs. Only those T cells with a TCR unable to bind self-peptide on self-MHC leave the thymus for the periphery.

Antigen-specific receptors on T cells are not identical to those on B cells (BCRs). The surface receptors of T cells are members of the Ig superfamily, with Ig-like domains. Each T cell is coated with a receptor originating in a single allele, so each receptor binds with a single specificity (CDR3 for antigens and CDR1-2 for MHCs). Clonotypic monoclonal antibodies can recognize TCR idiotypes. Each Ig chain has a variable and a constant region, and CDR of variable regions define the antigen-binding specificity and framework residues.

TCR is a heterodimer composed usually of α and β chains or, in a minority, γ and δ chains. The two chains are disulfide-bonded exterior to the T cell plasma membrane in a short extended stretch of amino acids that resembles the Ig hinge region. TCR, like Ig have very short cytoplasmic tails. Both TCR chains are glycosylated at sites on their V and C regions.

Each TCR has a single CDR3 binding site for antigen, while CDR 1 and CDR 2 bind peptide antigens on MHC. CDR3 is the most variable. Binding to CD4 (on helper T cells) or CD8 (on killer T cells) activates the T cell. Antigen-binding affinity is lower than that of Ig for native (self) antigen, but binding of MHC by the T cell membrane co-receptors CD4 or CD8 increases the binding affinity of the T cell for the antigen-MHC complex.

TCR expressed on the T cell membrane along with a signal transduction complex, CD3, that is called the invariant TCR chain. CD3 molecules on all T cells are formed from identical subunits, which are composed of three dimers: gamma epsilon (γε) or delta epsilon (δε), plus either two zetas (ζζ) or a zeta/eta (ζη) heterodimer. The γ and δ chains of CD3 are not identical to the molecules found in the γd TCR.

CD4 on helper T cells is a monomeric protein with four Ig-like domains, of which the two most distal domains are thought to bind Class II MHC β2 domain. CD8 is a disulfide-linked dimer, where the a and β chains each have one Ig-like domain connected by a long extended region to the transmembrane region. CD8 binds to the α3 region of Class I MHC. The cytoplasmic tails of both CD4 and CD8 associate with a cytoplasmic tyrosine kinase, Lck, to initiate signal transduction.

ф activation ф affinity maturation ф anergy ф antibodies ф antigen ф APCs סּ apoptosis ф B cells ф CD סּ cell-cycle control סּ cell membranes ф cellular response סּ cellular signal transduction ф class-switch recombination ф clonal selection ф complement system ф costimulation ~ cytokines סּ GPCRs ф helper T cell ф immune response ф immune tolerance ф isotype switching ф killer T cells ф leukocytes ф lymphocytes ф lymphokines ф macrophages ♦ MAPKs ф MHC ф monocytes ф neutrophils ф pathogens ф pattern-recognition receptors ♦ phosphatases ♦ phospholipases ~ phospholipase C-gamma ››› phosphorylation סּ phosphotransfer-mediated signaling pathways ♦ PKCs ♦ protein kinases ~ protein tyrosine kinases (PTKs) ф receptors סּ receptor proteins סּ receptor-mediated endocytosis ♦ receptor tyrosine kinases ф secondary antibody diversification ~ second messengers ♦ serine/threonine kinases ф signaling signaling gradients ¤ signaling molecules סּ signal transduction ф somatic hypermutation ф T cells ф thymus ф VDJ recombination

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Tables Fc receptors Immune Cytokines Immunoglobulins Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers

tags [Receptors] [BCR] [TCR] [ITAM] [signaling]

neuronal interconnections

2010-12-12T19:03:00.000-08:00

The neuron is the basic operating unit of the central nervous system. Inter-neuronal information processing, involving complex neural networks, provides the nervous system with its enormous functional capacity. The human brain contains about 10^(11) neurons*, which connect, via synapses, with an average of 1000 other neurons. In total, the human brain may contain somewhere between 10^(14) and 10^(15) synaptic connections. Neurotransmitter chemicals effect the connection between neurons, when they cross the gap between neurons and interact with specific receptor proteins. More than one hundred chemicals and a much larger number of receptors have been implicated in synaptic transmission. Some neurotransmitters are the targets of drug therapies. Receptor molecules are the targets of neurotoxic venomous substances.* 10^(11) is equivalent to a 10 followed by 11 zeros = 1,000,000,000,000

Depolarization of neuronal cell membranes beyond a necessary threshold results in action potentials which propagate along the soma/axon/dendrite to the pre-synaptic terminal bulb. At the pre-synaptic terminal, the wave of depolarization results in release of vesicle-stored neurotransmitters into the synaptic cleft. Released neurotransmitters bind to specific post-synaptic receptors that open ion channels, resulting in further depolarization and post-synaptic action potentials.

neurotransmission

2010-12-11T19:02:00.000-08:00

Roughly 10 small-molecule transmitters and over 50 recognized neuroactive peptides comprise the commonly recognized neurotransmitters, molecules involved in signalling between cells. A variety of macromolecules act as receptors for neurotransmitters and hormones (molecules that act at a distance from their production).

There exist numerous receptors for each neurotransmitter, so receptors play an important role in neurotransmission. Most neurotransmitter receptors belong to a class of proteins known as the serpentine receptors, or GPCRs, in which a characteristic trans-membrane structure spans the cell membrane seven times. Intracellular signalling is carried out by association of the neurotransmitter with G-proteins (small GTP-binding and hydrolyzing proteins), or with protein kinases, or by the receptor itself in the form of a ligand-gated ion channel (acetylcholine receptor). Neurotransmitter receptors are subject to ligand-induced desensitization whereby they become unresponsive upon prolonged exposure to their neurotransmitter. The NMDA receptor is a neural receptor that is expressed at excitatory glutamatergic synapses and is critical for normal brain function. At a cellular level, this receptor plays a pivotal role in triggering and controlling synaptic plasticity, and so is important for learning and memory.

Among the small-molecule neurotransmitters are: acetylcholine, 5 amines, and 3 or 4 amino acids. The purines adenosine, ATP, GTP, and their derivatives are also neurotransmitters. In addition to amines, amino acids, purines, and acetylcholine, fatty acids are candidates for neurotransmitter (endogenous canabinoid). The monoamine neurotransmitters include the catecholamines dopamine, epinephrine, and norepinephrine, which are derived from the amino acids phenylalanine and tyrosine. Serotonin, or 5-HT is a monoamine product of the amino acid tryptophan. The hydrophilic vasoactive amine histamine is derived from the amino acid histidine. Aspartate, glutamate, and GABA are also derived from amino acids (aspartic acid, glutamic acid). Glycine is the smallest amino acid, and acts as a neurotransmitter.

The catecholamine neurotransmitter dopamine is a precursor in the biosynthetic pathway to the other catecholamine neurotransmitters epinephrine (adrenaline) and norepinephrine (noradrenaline). Dopamine is synthesized in the body (predominantly in neurons and adrenals) by the decarboxylation of l-dopa by the enzyme aromatic-L-amino-acid decarboxylase. Dopamine beta hydroxylase converts dopamine to norepinephrine, and phenylethanoamine N-methyl transferase converts norepinephrine to epinephrine.

receptor-mediated endocytosis

2010-12-07T19:48:00.000-08:00

Receptor-mediated endocytosis creates receptosomes. Cells invaginate proteins and other types of ligands that have attached to specific receptors on the plasma membrane.

1. First, the protein or ligand binds to a specific receptor, forming a coated pit ("coated pit endocytosis"). The coated pit is a specialized membranous region coated with clathrin, which provides stability and aids the transport process.

2. Next, the coated pit next forms a coated vesicle and, shedding its clathrin coat, joins with other coated pits to form a receptosome.

• A • adhesion • C • cell membranes • cellular adhesion molecules • cellular signal transduction • centrioles • chemotaxis • chloroplast • cilia & flagella • communication • concentration gradients • cytokine receptors • cytoplasm • cytoskeleton • E • energy transducers • endoplasmic reticulum • endosomes • exosome • F • flagella & cilia • G • Golgi apparatus • GPCRs • H • hormones • I • ion channels • L • lysosome • M • meiosis • microtubules • mitosis • mitochondrion • N • Nitric Oxide • neurotransmission • neuronal interconnections • nuclear membrane • nuclear pore • P • pinocytosis • proteasome • protein degradation • pumps • R • receptor proteins • receptor-mediated endocytosis • S • second messengers • signaling gradients • signal transduction • spindle • structure • T • transport • two-component systems • U • ubiquitin • V • vacuole • vesicle •

receptor proteins

2010-12-07T19:47:00.000-08:00

Biologically active molecules (ligands) exert their physiological effect by activating or inducing 3D conformational changes in receptor proteins, which participate in signal transduction, cellular signaling, gene regulation, cellular proliferation and differentiation, or regulation of cellular metabolic processes.

Right - click to enlarge - Cartoon representation of a complex between DNA and the ZIF268 protein, containing 3 zinc finger motifs. The coordinating residues of the middle zinc finger are highlighted. Based on the x-ray structure of PDB 1A1L. Color coding: ZIF268: blue; DNA: orange; Zinc ions: green Author: Thomas Splettstoesser Download high-resolution version (1188x1114, 410 KB)

Receptor proteins are located in the cytoplasm, cell membrane, or nuclear membrane.
1. Cytoplasmic receptor proteins include those that respond to steroid hormones. Ligand activated receptors may enter the cell nucleus where they modulate gene expression.
2. Receptors within cell membranes may be peripheral or trans-membrane proteins. Many receptors for hormones and neurotransmission are trans-membrane proteins.
_a. Metabotropic receptors are coupled to G proteins, acting through various secondary pathways involving ion channels, enzymes such as adenylyl (adenylate) cyclases, and phospolipases, or PDZ domains.
_b. Ionotropic receptors are ligand-activated ion channels that permit entry of ions when the central pore is open.

סּ active transport סּ ion channels [] image - receptor proteins [] 3D image steroid receptor - Zn finger Џ animation - receptor protein :

There are more than 1200 individual human plasma membrane receptors in more than 20 families. Examples of receptor proteins/receptors include:
a. Guanine nucleotide-binding protein-coupled receptors (GPCRs) (metabotropic).
b. serine threonine kinases (SerThr Kinase) : TGF-β; MAPK cascade; phosphoinositol kinase-related kinase (PIKK) family - mTOR (FRAP1), ATM, ATR, DNA-PK
c. receptor tyrosine kinases (RTKs) : EGFR, Tie receptors, Eph RTKs,
d. cytokine receptors
e. integrins
f. TNF receptors : FAS

Џ beautiful Flash 8 animation - Inner Life of the Cell, which shows membrane adhesion-signaling, and Interpretation: Inner Life of the Cell Џ

• A • adhesion • C • cell membranes • cellular adhesion molecules • cellular signal transduction • centrioles • chemotaxis • chloroplast • cilia & flagella • communication • concentration gradients • cytokine receptors • cytoplasm • cytoskeleton • E • energy transducers • endoplasmic reticulum • endosomes • exosome • F • flagella & cilia • G • Golgi apparatus • GPCRs • H • hormones • I • ion channels • L • lysosome • M • meiosis • microtubules • mitosis • mitochondrion • N • Nitric Oxide • neurotransmission • neuronal interconnections • nuclear membrane • nuclear pore • P • pinocytosis • proteasome • protein degradation • pumps • R • receptor proteins • receptor-mediated endocytosis • S • second messengers • signaling gradients • signal transduction • spindle • structure • T • transport • two-component systems • U • ubiquitin • V • vacuole • vesicle •

. 7 TM receptors & GPCRs . Toll . NPR . Integrins . LDL receptors & LRP . Notch . Patched Plexins . Roundabout . RPTPs . RTKs . Ser/Thr Kinase receptors . TNF receptors . Cytokine 1 receptors . T-cell receptors . Cytokine 2 receptors . Netrin receptors .

receptor tyrosine kinases

2010-12-07T19:46:00.000-08:00

Receptor tyrosine kinases (RTKs) are involved in signal transduction, and process a variety of environmental and intercellular cues. By contrast, protein tyrosine kinases (PTKs) are non-receptor enzymes that catalyze the phosphorylation of tyrosine residues. Of the 91 protein tyrosine kinases identified, 59 are receptor tyrosine kinases and 32 are non-receptor, cellular tyrosine kinases. More than 70% of known oncogenes (cancers) and proto-oncogenes (development) code for PTKs.

: ABL : BTK : cellular protein tyrosine kinases : CSK : EGFR : extracellular domains : FAK & focal adhesion kinase : FPS : JAK : PTKs : Ras : receptor tyrosine kinases, RTKs : RTK functions : SFKs : STATs : SYK : tumors :

As central components of cell signaling networks, RTKs play crucial play crucial roles in physiological processes, such as embryogenesis, differentiation, neurite outgrowth, cell proliferation, anti-apoptotic signaling and death of cells (apoptosis). Some signaling molecules act as adhesion receptors, which cluster in focal adhesions upon ligand binding. Focal adhesions are rich in tyrosine phosphorylated proteins, coupling cell adhesion to signal transduction pathways in the cell. Various adhesion receptors, such as integrins, are closely linked to protein kinases and phosphatases.

RTKs comprise four domains:
1. extracellular ligand binding domain.
2. intracellular tyrosine kinase domain, with amino acid sequences in ATP binding and substrate binding regions highly conserved with those of cAMP-dependent protein kinase (cAPK, PKA).
3. intracellular regulatory domain.
4. transmembrane domain.

RTKs are anchored in the plasma membrane at the transmembrane domain, while the extracellular domains bind growth factors. Typically, extracellular domains comprise structural motifs including acidic regions, cadherin-like domains, cysteine-rich regions, discoidin-like domains, EGF-like domains, Factor VIII-like domains, fibronectin III-like domains, glycine-rich regions, immunoglobulin-like domains, kringle-like domains, and leucine-rich regions.

Tables Receptor Tyrosine Kinases(RTK) Cell signaling Cell Adhesion Molecules Immune Cytokines Receptor Signal Transduction Second Messengers

The intracellular kinase domains of receptor PTKs (RTKs) are divided into two classes:
a) those containing a stretch of amino acids separating the kinase domain, and
b) those in which the kinase domain is continuous.

Activation of the kinase is effected by binding of a ligand to the extracellular domain, which induces dimerization of the receptors. Activated receptors autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation. This auto-phosphorylation stabilizes the active receptor conformation and creates phosphotyrosine docking sites for proteins that transduce signals within the cell.

The epidermal growth factor (EGFR) family of receptor tyrosine kinases comprises four receptors: EGF-R (ErbB1), ErbB2 (Neu), ErbB3, and ErbB4.

Signaling proteins that bind to the intracellular domain of receptor tyrosine kinases in a phosphotyrosine-dependent manner include RasGAP, PI3-kinase, phospholipase C , phosphotyrosine phosphatase SHP and adaptor proteins such as Shc, Grb2 and Crk. Grb2 links focal adhesion kinase (FAK) to the Ras pathway when Grb2 is phosphorylated after binding to FAK. The 85 kDa subunit of the PI 3-kinase is also phosphorylated after binding to FAK. Thus, FAK is a key component in the assembly of focal contact structures that influence cytoskeletal organization and signal transduction. [] 3D phospholipase-C /PDGF-receptor [] inactive and active Ras molecular switch []

In contrast to receptor-PTKs (RTKs), cellular PTKs are located in the cytoplasm, the nucleus, or are anchored to the inner leaflet of the plasma membrane. Cellular PTKs are grouped into eight families: SRC, JAK, ABL, FAK, FPS, CSK, SYK and BTK, each with several members. Except for homologous kinase domains (Src Homology 1, or SH1 domains), and some protein- protein interaction domains (SH2 and SH3 domains), the PTK families share little structurally. Of the cellular PTKs with known functions, many, such as SRC, are involved in cell growth. FPS PTKs are involved in cellular differentiation, ABL PTKs participate in growth inhibition, and FAK activity is associated with cell adhesion. Some members of the cytokine receptor pathway interact with JAKs, which phosphorylate the transcription factors, STATs.

PTKs are hyperactivated in several human solid tumors and hematological malignancies, and elevated levels contribute to tumourigenesis factors such as hyperplasia, survival, invasion, metastasis and angiogenesis. PTKs of the Src family (SFKs) are activated and overexpressed in approximately 80% of colon tumors; EGFR family PTKs are overexpressed/activated in the most breast and lung carcinomas and primary glioblastomas; and, EpH receptor PTKs are overexpressed in most melanomas.

* A ligand is any molecule that binds reversibly and specifically to a protein. In the case of protein transcription factors, the ligand is DNA. ↑ סּ receptor proteins סּ

Tables Receptor Tyrosine Kinases(RTK) Cell signaling Cell Adhesion Molecules Immune Cytokines Receptor Signal Transduction Second Messengers

• phosphotransfer-mediated signaling pathways • Protein Kinase Signaling Networks • receptor tyrosine kinases • Receptor Tyrosine Kinases (RTKs) • signaling gradients • two-component systems • animation MAPK signal transduction : animation G-protein :: ABL : BTK : cellular protein tyrosine kinases : CSK : EGFR : extracellular domains : FAK & focal adhesion kinase : FPS : JAK : PTKs : Ras : receptor tyrosine kinases, RTKs : RTK functions : SFKs : STATs : SYK : tumors :

Syk tyrosine kinase and Src homology (SH) 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76) are critical signaling mediators activated downstream of both immunoreceptor tyrosine-based activation motif (ITAM)-containing immunoreceptors and integrins.[r]

Signaling pathways:
Pathway ABC transporters : Pathway Phosphotransferase system (PTS) : Pathway Two-component system : Pathway MAPK signaling pathway : Pathway Wnt signaling pathway : Pathway Notch signaling pathway : Pathway Hedgehog signaling pathway : Pathway TGF-beta signaling pathway : Pathway VEGF signaling pathway : Pathway Jak-STAT signaling pathway : Pathway Calcium signaling pathway : Pathway Phosphatidylinositol signaling system : Pathway mTOR signaling pathway : Pathway Neuroactive ligand-receptor interaction : Pathway Cytokine-cytokine receptor interaction : Pathway ECM-receptor interaction : Pathway Cell adhesion molecules (CAMs) :

: Evolution of Protein Kinase Signaling : ▲ Top ▲

regulatory proteins

2010-12-07T19:25:00.000-08:00

Genetic regulatory proteins bind to segments of DNA and bring about gene regulation. Non-genetic classes of regulatory proteins include those target, effector proteins that are involved in special cellular functions such as signaling as receptor proteins and pumps, adhesion, chemotaxis, cellular transport and active transport, and metabolic regulation, including enzymatic action and protein degradation.

Repressors and other regulatory proteins probably search for target sequences by binding to DNA and scanning its major groove. Most regulatory proteins recognize DNA because they can slide along it while searching for a specific target sequence. Such a search would be much slower for a protein that cannot bind DNA. [s]

Tables Regulatory Proteins Sequences Gene Regulation in E.coli Second Messengers Cell signaling Cell Adhesion Molecules Enzymes Function Krebs Cycle Enzymes Cofactors of Krebs Cycle

Most gene regulation proteins are single proteins, often homodimers or homotetramers, which bind to two ligands: a. a metabolic intermediate, and b. a cis-acting gene regulation element.

Most of the known phosphorylated response regulators employ the two-component system to stimulate or repress the transcription of specific targetted genes.

Allosteric regulatory proteins alteration of metabolic pathways utilizing end product repression, enzyme induction, and catabolite repression. Like allosteric enzymes, these proteins alter their levels of activity in response to ligand-binding induced conformational (shape) changes. The allosteric or effector ligand is a small molecule that affects the active site by binding to the allosteric site. In the case of allosteric regulatory proteins, the active site is a DNA binding site, which binds, only when active, to a specific sequence of DNA. By binding to specific DNA sequences, the allosteric regulatory protein impacts levels of gene expression.

Items • allosteric enzymes • anabolism and catabolism • Control of prokaryotic gene expression • gene regulation • Interactions in Bacteria • phosphorylation • Phosphorylation switches in bacteria • phosphotransfer-mediated signaling pathways • Protein Kinase Signaling Networks • signaling gradients • signal transduction • two-component systems ••
Tables Regulatory Proteins Sequences Gene Regulation in E.coli Cell signaling Receptor Tyrosine Kinases(RTK) Second Messengers Phosphate-handling Enzymes Second Messengers
Cell signaling Immune Cytokines Electron Transport Chain vs Oxidative Phosphorylation Enzymes Function Krebs Cycle Enzymes Cofactors of Krebs Cycle Phosphate-handling enzymes

Specific Enzymes/Types : ·· A · adenylyl (adenylate) cyclase · allosteric enzymes · AP endonuclease (Ape1) ·· C · cAMP-dependent protein kinase · cyclin-dependent kinases ·· D · DAGKs · diacyl glycerol kinases · DNA glycosylase · DNA ligase · DNA Ligase I · DNA polymerases · DNA polymerase I · DNA polymerase beta · DNase IV · · E · exonuclease 1 · exosome ·· F · focal adhesion kinases (FAKs) · Fen1 · Flap Endonuclease FEN-1 · G · guanylate cyclases · guanyl cyclase ·· H · hOGG1 · hOGG1 oxoG repair ·· I · inducible transcription factors ·· L · LigIII · · M · MAP kinase · mitogen activated protein kinases · Msh2-Msh3 · MutS, MutL, and MutH ·· O · 8-oxoguanine glycosylase · oxoG repair hOGG1 ·· P · PCNA · phosphatases · phosphodiesterases · phospolipases · phospholipase C-gamma · PLC-G · protein kinase A · protein kinase C · protein tyrosine kinases (PTKs) · receptor tyrosine kinases · R · RNA polymerase · Replication factor C · reverse transcriptase · ribozymes · RNA polymerase II · RTKs ·· S · serine/threonine kinases · spliceosomal-mediated RNA trans-splicing · SMaRT ·· T · trans-splicing ribozymes ·· U · UvrD ·· X · XRCC1 ·

Specific proteins/types : ·· C · cAMP receptor binding protein · cofactor · core histones H2A, H2B, H3, and H4 · CRE-binding protein CREB · cytokines ·· E · elongation factor EF ·· G · general transcription factors ·· H · helicases : Helicase II · heterochromatin · histone · HP1 · I · inducible transcription factors · L · · LexA repressor ·· M · mCAT2 receptor · motor proteins ·· N · nucleosome ·· P · PcG proteins · PCNA · Polycomb group · proteome ·· R · RecA · regulatory proteins · repressor proteins · Receptor Tyrosine Kinases (RTKs) · ribosomes · RPA ·· S · serine rich (SR) splicing factors · silencers · Ski7p · small nuclear ribonucleoproteins (snRNPs) · spliceosome · SR (serine rich) splicing factors ·· T · TATA binding protein · TBP · trans-acting factors · trithorax group (trxG) ·· U · ubiquitin (Ub) · UPF1 UPF2 · upstream transcription factors ·

signal transduction

2010-12-06T03:26:00.000-08:00

Cellular signal transduction involves the conversion of one signal or stimulus (mechanical or chemical) to another. The transduction process is usually performed by enzymes in association with second messengers.

▼ : 7TM receptors : classes of receptors : controlled activities : coupling : DAG : diacylglycerol : DGKzeta : extracellular signals : GEFs : G-protein coupled receptors : guanine nucleotide-binding protein-coupled receptors : GPCR families : GPCRs : heptahelical receptors : hormone receptors : HREs : intracellular signals : intracellular receptors : intercellular signals : IP3 : kinase inhibitors : ligands : phospholipases : phospholipids : PI3K : PKCs : protein kinases : Ras : RasGRP : receptor classes : serpentine receptors : targets for control : 7TM receptors : ▼

Extracellular signals impinge upon specialized membranous receptors. Sensory transduction involves the conversion of mechanical or chemical stimuli to cellular signals or neurophysiological signals. Intracellular signals enable communication within cells, while intercellular signals enable communication between cells.

Tables Cell Adhesion Molecules Cell signaling Immune Cytokines Receptor Tyrosine Kinases (RTKs) Second Messengers

Chemical signals (ligands) include :
1. neurotransmitters : acetylcholine, dopamine, epinephrine, GABA, glycine, norepinephrine, serotonin (5HT), etc.
2. hormones
3. phospholipids
4. growth factors
5. nutrients

Classes of receptors:
1. Membrane-penetrating receptors possessing/connected to intrinsic enzymatic activity:
…….a) receptor tyrosine kinases (RTKs) capable of autophosphorylation as well as phosphorylation of other substrates (incl. EGF, FGF, insulin, PDGF receptors),
…….b) tyrosine phosphatases (CD45),
…….c) guanylate cyclases (natriuretic peptide receptors),
…….d) serine/threonine kinases (activins, inhibins, bone morphogenetic proteins (BMPs), TGF-beta receptors).
…….e) receptors coupled to intracellular tyrosine kinases by direct protein-protein interactions: 'Multiprotein signaling networks create focal points of enzyme activity that disseminate the intracellular action of many hormones and neurotransmitters. Accordingly, the spatio-temporal activation of protein kinases and phosphatases is an important factor in controlling where and when phosphorylation events occur. Anchoring proteins provide a molecular framework that orients these enzymes towards selected substrates. A-kinase anchoring proteins (AKAPs) are signal-organizing molecules that compartmentalize the cAMP dependent protein kinase, phosphodiesterases, and a variety of enzymes that are regulated by second-messengers.'[s].

Phospholipases and phospholipids participate in transmission of ligand-receptor induced signals from the plasma membrane to intracellular proteins, primarily PKC, which is maximally active in the presence of calcium ion and diacylglycerol. PKC activity is mediated by receptors that are coupled to activation of phospholipase C-gamma (PLC-gamma), which contains SH2 domains that enable it to interact with tyrosine phosphorylated RTKs. PI-3K is tyrosine phosphorylated and activated by various RTKs and receptor-associated PTKs. PI-3K is activated by the PDGF, EGF, insulin, IGF-1, HGF and NGF receptors. The p85 subunit of PI-3K is activated by tyrosine phosphorylation, but only the 110 kDa subunit is enzymatically active.

Phospholipases D and A2 (PLD, PLA2) sustain the activation of PKC through their hydrolysis of membrane phosphatidylcholine (PC). Activation of PLC-gamma results in hydrolysis of membrane phosphatidylinositol bisphosphate (PIP2), which leads to an elevation of intracellular DAG and inositol trisphosphate (IP3), which interacts with intracellular membrane receptors to effect release of stored calcium ions (PKC is maximally active in the presence of second messengers, calcium ions and diacylglycerol).

Diacylglycerol (DAG) is an intracellular messenger, which accumulates transiently in cells exposed to growth factors or other stimuli. Cellular responses such as growth and differentiation are impacted by the binding of DAG to PKC, thus activating PKC. Diacylglycerol kinases (DGKs) are responsible for eliminating the function of diacylglycerol (DAG) and for producing phosphatidic acid (PA) (both molecules are connected to cancer).

DGKzeta regulates factors that promote activity of the oncogene product, Ras, the activity of which must be precisely regulated lest abnormal cellular proliferation result. An estimated 30% of human tumors have an activating mutation of the Ras gene. Guanine nucleotide exchange factors (GEFs) activate Ras by facilitating GTP binding. Abnormally high levels of the nucleotide exchange factor, RasGRP can lead to malignant transformation. RasGRP has a diacylglycerol (DAG)-binding domain and its exchange factor activity depends on local availability of the signaling molecule DAG. Diacylglycerol kinases (DGKs) remove DAG from the cell by converting DAG to PA. DGKzeta, but not other DGKs, can completely eliminate Ras activation induced by RasGRP, and diacylglycerol kinase activity is required for this mechanism.

2. Serpentine receptors, guanine nucleotide-binding protein-coupled receptors, or GPCRs, in which a characteristic trans-membrane structure spans the cell membrane seven times. Intracellular signalling is carried out by association of the neurotransmitter with G-proteins (small GTP-binding and hydrolyzing proteins), which leads to generation of second messengers. GTP-hydrolytic activity of G-proteins is regulated by GTPase activating proteins, GAPs. Ras, is a proto-oncogenic G-protein involved in carcinogenesis. Other cancer-active G-proteins include the gene products of the neurofibromatosis type-1 (NF1) susceptibility locus and the BCR locus (break point cluster region gene).

There are several families of GPCRs, including:
(a) GPCRs that modulate adenylate cyclase activity
(b) GPCRs that activate phospholipase C-gamma, leading to hydrolysis of polyphosphoinositides (such as PIP2) and generating the second messengers, diacylglycerol (DAG) and inositol trisphosphate (IP3). This class of receptors includes receptors for angiotensin, bradykinin and vasopressin.
(c) Photoreceptors coupled to a G-protein (transducin) that activates a phosphodiesterase, depressing the level of second messenger cGMP. The drop in cGMP causes closing of a Na+/Ca2+ ion channel, leading to hyperpolarization of the cell.

3. Intracellular receptors that migrate to the nucleus after binding to the ligand – here the ligand-receptor complex directly affects gene transcription. Hormone receptors are cytoplasmic proteins that bypass membrane-bound signal transduction pathways – receptors for lipophilic steroid/thyroid hormones, the glucocorticoid, vitamin D, retinoic acid and thyroid hormones. All hormone receptors are capable both of binding hormone and of directly activating gene transcription (bi-directional). After binding the hormonal ligand, the hormone-receptor complex translocates to the nucleus and binds to specific DNA sequences (hormone response elements, HREs), resulting in altered transcription rates of the associated gene.

Coupling of ligand-receptor interactions to intracellular events
1. phosphorylations by tyrosine kinases and/or serine/threonine kinases – two-component systems

Intracellular events controlled by signaling:
1. gene expression (transcription)
2. chemotaxis
3. cellular growth, proliferation, and differentiation (tyrosine and serine/threonine phosphorylation)

Protein kinases are targetted by pharmaceuticals because PKs play a variety of roles in disease states. Kinase inhibitors bind to the kinase in at least four different binding modes:
(1) direct competition with ATP at the ATP binding site;
(2) engagement of an adjacent allosteric binding site in the ATP pocket, which is usually accessible when the activation loop is in the inactive conformation; and
(3) binding at sites remote from the ATP site (but still close to the ATP) that impact kinase activity;
(4) binding outside of the ATP binding pocket (truly allosteric).

Kinases can escape inhibition by mutating key residues in their catalytic domain, thus becoming resistant to the kinase inhibitors. Those kinase that have or gain functional mutations may be more sensitive or resistant to inhibition by kinase inhibitors than is the wt form of the kinase.

▲: 7TM receptors סּ adhesion סּ cell membranes סּ chemotaxis : classes of receptors : controlled activities : coupling : DAG ~ DAG ~ DAGKs ~ diacylglycerol ~ diacyl glycerol kinase : diacylglycerol : DGKzeta : extracellular signals : GEFs : G-protein coupled receptors : guanine nucleotide-binding protein-coupled receptors : GPCR families : GPCRs סּ GPCRs סּ GPCR families s : heptahelical receptors סּ hormones: hormone receptors : HREs : intracellular signals : intracellular receptors : intercellular signals : IP3 : kinase inhibitors : ligands סּ microtubules סּ migration ₪ molecular switches סּ neurotransmission סּ neuronal interconnections : phospholipases ~ phospholipase C-gamma : phospholipids : PI3K : PKCs : protein kinases : Ras : RasGRP ¤ Ras : receptor classes סּ receptor-mediated endocytosis סּ receptor proteins : serpentine receptors ~ signaling items ¤ signaling molecules : targets for control : 7TM receptors : ▲

Chemotaxis • GPCRs • GPCR families • hormones • neurotransmission • Nitric Oxide • neuronal interconnections • phosphotransfer-mediated signaling pathways • Protein Kinase Signaling Networks • receptor tyrosine kinases • Receptor Tyrosine Kinases (RTKs) Tables Cell signaling Cell Adhesion Second Messengers Immune Cytokines Apoptosis vs Necrosis Apoptosis Malignant Transformation Oncogenes Proto-oncogenes Regulatory Proteins Sequences • signaling gradients • two-component systems • animation MAPK signal transduction : more :

Signaling pathways:
Pathway ABC transporters : Pathway Phosphotransferase system (PTS) : Pathway Two-component system : Pathway MAPK signaling pathway : Pathway Wnt signaling pathway : Pathway Notch signaling pathway : Pathway Hedgehog signaling pathway : Pathway TGF-beta signaling pathway : Pathway VEGF signaling pathway : Pathway Jak-STAT signaling pathway : Pathway Calcium signaling pathway : Pathway Phosphatidylinositol signaling system : Pathway mTOR signaling pathway : Pathway Neuroactive ligand-receptor interaction : Pathway Cytokine-cytokine receptor interaction : Pathway ECM-receptor interaction : Pathway Cell adhesion molecules (CAMs) : Orthology Transporters (+diseases) : Orthology Two-component system : Orthology Receptors and channels (+diseases) : Orthology Cytokines : Orthology Cell adhesion molecules (CAMs) : Orthology CAM ligands : Orthology CD molecules : Orthology GTP-binding proteins :

▲ Top ▲

Atheism Reception

2008-01-01T13:21:00.000-08:00

A-Deistic
Adeistic
Black Out
cosmic
Eine Kleine Nattermusing
eMusings
eVolition
Galaria
Godborygmi
Godspell Follies
Gray Matters
MetaThoughts
Mimble Wimble
Naturalism
BLogodaedaly
palimpsest
Salient
Science of Evolution
Sechuam
Sintheist
Tabula Flexuosa
The Scarlet A
Weltschauung

receptive

2007-12-01T01:00:00.000-08:00

Associated science sites • Abiogenesis and Evolution • Algorithms of Evolution • Archea Eubacteria • Cancer • Cell Biology • Complex Systems • Cyanobacteria • Diagrams Tables • Endosymbiosis • Enzymes • Evo Devo • Evolution in Action • Fat • Geology • Glossary • Immunology • Life Chemistry • Medical Science • Mechanisms of Evolution • Molecule • Molecular Biology • Molecular Paths • Neurosciences • Organics • Origin of Life • Paleogeology • Pathways • Photosynthesis • Protein • Receptor • Rocks & Minerals • SET • Signaling • Sleep • Stem & Progenitor Cells • Stromatolites • Taxonomy Phylogeny • Tissue • Virus • And some philosophy/general interest sites • A-Deistic • Adeistic • Black Out • cosmic • Eine Kleine Nattermusing • eMusings • eVolition • Galaria • Godborygmi • Godspell Follies • Gray Matters • MetaThoughts • Mimble Wimble • Naturalism • BLogodaedaly • palimpsest • Salient • Science of Evolution • Sechuam • Sintheist • Tabula Flexuosa • The Scarlet A • Weltschauung •

Signaling & Receptors

2006-12-16T15:22:00.000-08:00

Receptors are molecules that receive signals by binding ligands. Signal transduction is the process of converting that signal from one form to another, ultimately altering an intracellular process, as in metabolic regulation, or an intranuclear process, such as gene expression.

o

1990-01-01T01:00:00.001-08:00

• Abiogenesis and Evolution • Algorithms of Evolution • Archea Eubacteria • Cancer • Cell Biology • Complex Systems • Cyanobacteria • Diagrams Tables • Endosymbiosis • Enzymes • Evo Devo • Evolution in Action • Fat • Geology • Galaria • Glossary • Godspell Follies • Harper's Folly • Immunology • Life Chemistry • Medical Science • Mechanisms of Evolution • Mimble Wimble • Molecule • Molecular Biology • Molecular Paths • Organics • Origin of Life • Paleogeology • Pathways • Photosynthesis • Protein • Receptor • Rocks & Minerals • SET • Signaling • Sleep • Stem & Progenitor Cells • Stromatolites • Tabula Flexuosa • Taxonomy Phylogeny • Tissue • Virus •

site map

1990-01-01T00:00:00.000-08:00

◊◊ cell signaling
◊◊ cell-surface receptors
◊◊ GPCR
◊◊ hormones
◊◊ immune receptors
◊◊ immune signaling
◊◊ intracellular receptors
◊◊ lymphocyte receptors
◊◊ neuronal interconnections
◊◊ neurotransmission
◊◊ receptor-mediated endocytosis
◊◊ receptor proteins
◊◊ receptor tyrosine kinases
◊◊ regulatory proteins
◊◊ signal transduction