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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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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signal transduction

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 :

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