cell signaling

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 :

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cell-surface receptors

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.

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GPCR

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) :

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hormones

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.

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immune receptors

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

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

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intracellular receptors

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)

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lymphocyte receptors

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]

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