Integrin-mediated cell adhesion
Cell migration is a coordinated process that involves rapid changes in the dynamics of
actin filaments, together with the formation and disassembly of cell adhesion sites.
External stimuli that control cell migration are transduced into intracellular
biochemical signals through the interactions of transmembrane integrins that bind to the
extracellular matrix (ECM) proteins .
Integrins are heterodimeric cell surface adhesion receptors formed by two
noncovalently associated subunits, alpha and beta. There are 18 alpha and 8 beta subunits
that associate to form 24 different heterodimers . Most integrins
recognize several ECM proteins, such as Laminin 1,
Fibronectin and Collagen
(types I, II and IV), whereas
recognizes only Fibronectin .
The ECM, integrins and the cell cytoskeleton interact at sites called focal contacts
. The integrin-binding proteins Paxillin and
Talin recruit Focal adhesion kinase
(FAK1) and a cytoskeletal protein
Vinculin to focal contacts.
Alpha-actinin is a cytoskeletal protein that binds to
Vinculin and crosslinks Actin
in actomyosin stress fibers and tethers them to focal contacts. Phosphorylation of
Alpha-actinin by FAK1
reduces the crosslinking of stress fibers and
prevents maturation of the focal contacts .
Vinculin transiently recruits the Actin-related protein
complex (Arp2/3) to new sites
of integrin aggregation . Arp2/3 complex
nucleates new Actin filaments from the sides of preexisting
filaments. This interaction requires phosphorylation of the
Arp2/3 complex by p21-activated kinase 1
(PAK1) that leads to
polymerization of Actin .
Zyxin is an Alpha-actinin
and stress-fiber-binding protein found in mature contacts.
Activated Talin binds to
enzyme Phosphatidylinositol phosphate kinase type I gamma (PIPKI
gamma) and activates it. PIPKI gamma also can
be stimulated by tyrosine-protein kinase c-Src  and FAK1 phosphorylation .
PI(4,5)P2 enhances Talin
association with Integrins and stimulates the direct
transient interactions of diverse cytoskeleton actin-binding proteins
and Wiskott-Aldrich syndrome-like
(N-WASP), thereby regulating
Actin polymerization by stimulating the actin-nucleating
activity of the Arp2/3 complex , .
Integrin clustering promotes
FAK1 autophosphorylation at Tyr397, thereby creating a
binding site for c-Src. Phosphorylation of
FAK1 at Tyr576 and Tyr577 mediated by
c-Src maximizes catalytic activity of
FAK1. Phosphorylation of FAK1 at Tyr925
mediated by c-Src creates a binding site for the Growth
factor receptor-bound protein 2 (GRB2), thereby leading to
the activation of the Extracellular signal-regulated kinase-1/2
(ERK1/2). The GRB2 binding can
displace Paxillin from its binding sites on the
FAK1, and Tyr925-phosphorylated
FAK1 might be selectively released from the focal
ERK2 phosphorylates FAK1 at
Ser910 and decreases Paxillin binding to
FAK1. Within focal contacts,
phosphorylation of Paxillin promotes
ERK2 binding. ERK2-mediated
phosphorylation of Paxillin can facilitate
FAK1 binding to Paxillin and
enhance FAK1 activation. Thus, there might be a regulatory
cycle in which c-Src- and
ERK2-mediated phosphorylation of
FAK1 promotes its release from focal contacts and
ERK2-mediated phosphorylation of
Paxillin promotes the association of non-phosphorylated
FAK1 with Paxillin at new or
growing focal contact sites . Finally, local
ERK2-mediated phosphorylation and activation of Myosin light
chain kinase (MYLK1) together with inactivation of
PAK1 contribute to cell-matrix adhesion dynamics .
Active FAK1-c-Src complex
facilitates binding of the CRK-associated substrate
FAK1 and its subsequent phosphorylation by
c-Src. v-Crk sarcoma virus CT10 oncogene homolog
(CRK) binds to phosphorylated
p130Cas and facilitates activation of Ras-related C3
botulinum toxin substrate 1 (Rac1) by the Guanine nucleotide
exchange factor Dock180 (DOCK1) . Activation
of Rac1 leads to membrane ruffles, formation of lamellipodia
and cell migration .
Rac1 downstream effector PAK1
phosphorylates diverse target proteins, thereby leading to the activation
of LIM-kinase 1 (LIMK1) , inhibition of Myosin light chain kinases
(MLCK) , activation of Myosin
regulatory light chains (MRLC)  and
activation of the Arp2/3 complex .
FAK1 phosphorylates and activates the Ras
protein-specific guanine nucleotide-releasing factor 1
(RASGRF1), an activator of Ras homolog gene family member
, whereas active c-Src in the
complex with FAK1
phosphorylates and activates GTPase-activating protein Glucocorticoid receptor DNA
binding factor 1 (p190RhoGAP),
a RhoA inhibitory protein .
FAK1 thereby may regulate cytoskeletal dynamics by
modulating activity of RASGRF1,
p190RhoGAP, and their effector RhoA .
RhoA downstream Rho-associated kinases 1 and
2 (ROCK) directly phosphorylate
LIM-kinase 2 (LIMK2). LIMK1 and
LIMK2 phosphorylate actin-associated protein
Cofilin. Cofilin exhibits
actin-depolymerizing activity followed by reorganization of the
Actin cytoskeleton , .
The activated ROCK kinases also phosphorylate and
inactivate the Myosin light chain phosphatase (MLCP)  that attenuates phosphorylation of the Myosin light chains
(MELC) and MRLC
 and formation of actomyosin stress fibers.
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