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
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
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
DAG activates protein kinase C
PKC-epsilon, that phosphorylates the cytoplasmatic tail of
the beta-1 integrin subunit
PKC-epsilon is also
activated in G-protein alpha-12 family signaling pathway
. G-protein alpha-12 family subunits, in
turn, are stimulated by the activity of TBXA2R  and AGTR1.
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
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
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
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
. 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
. 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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