Pathway Map Details
Cell adhesion_Integrin inside-out signaling
Object list (links open in MetaCore):
alpha-5/beta-1 integrin, Ca('2+) endoplasmic reticulum lumen, FAK1, G-protein alpha-12 family, alpha-2/beta-1 integrin, IP3 receptor, Angiotensin II, Thrombin, Fibronectin, Fibrinogen, IP3, TBXA2R, PKC-epsilon, Actin cytoskeletal, PtdIns(3,4,5)P3, Collagen II, alpha-L/beta-2 integrin,
Integrin inside-out signaling
The integrin family of transmembrane adhesion receptors mediates both cell-cell and cell- extracellular matrix (ECM) adhesion. One important, rapid and reversible mechanism for regulating adhesion is increasing the affinity of integrin receptors for their extracellular ligands (integrin activation). This is controlled by intracellular signals that, through their action on integrin cytoplasmic domains, induce conformational changes in integrin extracellular domains that result in increased affinity for ligand (inside-out signaling) , .
Several such inside-out signal pathways could be activated by a host of G-protein-coupled receptors (GPCRs), including the Thromboxane A2 receptor ( TBXA2R ), Thrombin receptors PAR1 and PAR4, Angiotensin II receptor type-1 ( AGTR1 ), and receptor for the C-X-C chemokine SDF-1 ( CXCR4 ).
Ligand binding triggers conformational changes that promote receptor/G-protein coupling and catalyzes the exchange of GTP for GDP on the G-alpha subunit of the heterotrimeric G protein, leading to dissociation of the GTP-bound G-alpha subunit from the G - beta/gamma subunit heterodimer .
The G alpha-q family of G-proteins ( G-protein alpha-q/11 ) and G-protein beta/gamma subunits activate different phosphoinositide-specific phospholipase C PLC-beta isozymes , . These enzymes in turn catalyze the hydrolysis of phosphatidylinositol 4,5-bisphosphate ( PtdIns(4,5)P2 ) to inositol 1,4,5-trisphosphate ( IP3 ) and diacylglycerol ( DAG ) .
IP3 stimulates Ca(2+) release from endoplasmic reticulum storage sites via the inositol 1,4,5-trisphosphate receptor ( IP3 receptor ) . Ca(2+), in turn, activates diverse downstream targets, including Calmodulin  and Calmyrin .
DAG activates protein kinase C PKC-epsilon, that phosphorylates the cytoplasmatic tail of the beta-1 integrin subunit ( ITGB1 ) .
The Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, gamma isoform ( PI3K cat class IB, gamma ) is activated by G-protein beta/gamma subunits upon stimulation of GPCRs AGTR1 and CXCR4. PI3K cat class IB (p110-gamma) phosphorylates the membrane lipid PtdIns(4,5)P2 to generate phosphatidylinositol 3,4,5-trisphosphate PtdIns(3,4,5)P3 .
Tyrosine-protein kinase c-Src is activated by G-protein alpha-q/11, G-protein alpha-12 family, and G-protein beta/gamma subunits. In most cell types, c-Src stimulation is involved in GPCR-mediated activation of the Focal adhesion kinase FAK1 and the mitogen-activated protein kinases ERK1 / 2 .
Talin, a major cytoskeletal Actin -binding protein, plays a crucial role in integrin activation. Talin binding to integrin beta-1 ( ITGB1 ), integrin beta-2 (ITGB2 ), integrin beta-3 ( ITGB3 ) cytoplasmic tails induces conformational changes in their extracellular domains, increasing integrin affinity for ligands. Mechanisms that regulate Talin binding may therefore control integrin activation .
The binding of PtdIns(4,5)P2 to Talin induces a conformational change that enhances its association with integrin beta subunits. Talin binds to and activates the PtdIns(4,5)P2 -producing enzyme: phosphatidylinositol phosphate kinase type I gamma ( PIPKI gamma ). Therefore, Talin can stimulate PtdIns(4,5)P2 production that enhances Talin - Integrin interactions, which suggests that PIPKI gamma may positively regulate integrin activation. PIPKI gamma is also stimulated by c-Src  and FAK1 phosphorylation . However, PIPKI gamma and integrin beta-1 tails compete for overlapping binding sites on the Talin and so, under some conditions, PIPKI gamma might inhibit integrin activation by displacing Talin from beta-1 tails .
PtdIns(4,5)P2 also stimulates the transient, direct interactions of diverse cytoskeleton actin-binding protein and couple adhesion to Actin assembly .
The integrin beta-1 binding protein ICAP-1 inhibits Integrin - Talin association . Calcium/calmodulin-dependent protein kinase II CaMK II phosphorylates ICAP-1 and this phosphorylation negatively regulates integrin-mediated processes .
Beta-3-endonexin ( NRIF3 ) binds specifically to ITGB3 and activates alpha-IIb/beta-3 integrin . However, in the absence of Talin, this activation is very weak. Therefore, NRIF3 may cooperate with Talin during alpha-IIb/beta-3 integrin activation in platelets .
Calcium - and integrin-binding protein Calmyrin, which interacts directly with the alpha-IIb ( ITGA2B ) tail, inhibits alpha-IIb/beta-3 integrin activation by competing with talin for binding to integrin .
Guanine nucleotide exchange factors Cytohesin-1 and Cytohesin-3, activated by PI(3,4,5)P3, bind ITGB2 which leads to an increase cell adhesion through an affinity-independent processes, such as integrin clustering, rather than integrin activation .
Intracellular signals induce conformational changes in the integrin extracellular domains that result in their increased affinity for ligands, focal adhesion formation and integrin signal transduction (outside-in signaling) .
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