Pathway Map Details

Cell adhesion_Integrin-mediated cell adhesion and migration

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FAK1, alpha-3/beta-1 integrin, MLCP (reg), RASGRF1, MLCK, PIPKI gamma, GRB2, Actin cytoskeletal, Laminin 1, N-WASP, PI(4)P, ERK1/2, MELC, p190RhoGAP, MLCP (cat), Paxillin, c-Src, Myosin heavy chain, MRLC,, alpha-11/beta-1 integrin, alpha-7/beta-1 integrin, LIMK2, p130CAS, Cofilin, Fibronectin, Zyxin, Alpha-actinin, ROCK, alpha-1/beta-1 integrin, Vinculin, Collagen I, Arp2/3, LIMK1, PtdIns(4,5)P2, alpha-2/beta-1 integrin, MYLK1, alpha-5/beta-1 integrin, Collagen II, Rac1, alpha-10/beta-1 integrin, DOCK1, CRK, Collagen IV, RhoA, Talin, PAK1, ERK2


Integrin-mediated cell adhesion and migration

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 [1].

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 [2]. Most integrins recognize several ECM proteins, such as Laminin 1, Fibronectin and Collagen ( types I, II and IV ), whereas alpha-5/beta-1 integrin recognizes only Fibronectin [3].

The ECM, integrins and the cell cytoskeleton interact at sites called focal contacts [4]. 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 [5]. Vinculin transiently recruits the Actin-related protein complex ( Arp2/3 ) to new sites of integrin aggregation [6]. 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 [7].

Zyxin is an Alpha-actinin and stress-fiber-binding protein found in mature contacts.

Activated Talin binds to Phosphatidylinositol-4,5-bisphosphate ( PI(4,5)P2) -producing enzyme Phosphatidylinositol phosphate kinase type I gamma ( PIPKI gamma ) and activates it. PIPKI gamma also can be stimulated by tyrosine-protein kinase c-Src [8] and FAK1 phosphorylation [9]. PI(4,5)P2 enhances Talin association with Integrins and stimulates the direct transient interactions of diverse cytoskeleton actin-binding proteins Vinculin, Alpha-actinin and Wiskott-Aldrich syndrome-like ( N-WASP ), thereby regulating Actin polymerization by stimulating the actin-nucleating activity of the Arp2/3 complex [10], [7].

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 contacts.

ERK2 phosphorylates FAK1 at Ser910 and decreases Paxillin binding to FAK1. Within focal contacts, FAK1 - c-Src -mediated 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 [1]. Finally, local ERK2 -mediated phosphorylation and activation of Myosin light chain kinase ( MYLK1 ) together with inactivation of PAK1 contribute to cell-matrix adhesion dynamics [11].

Active FAK1 - c-Src complex facilitates binding of the CRK-associated substrate ( p130Cas ) to 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 ) [12]. Activation of Rac1 leads to membrane ruffles, formation of lamellipodia and cell migration [13].

Rac1 downstream effector PAK1 phosphorylates diverse target proteins, thereby leading to the activation of LIM-kinase 1 ( LIMK1 ) [14], inhibition of Myosin light chain kinases ( MLCK ) [15], activation of Myosin regulatory light chains ( MRLC ) [16] and activation of the Arp2/3 complex [17].

FAK1 phosphorylates and activates the Ras protein-specific guanine nucleotide-releasing factor 1 ( RASGRF1 ), an activator of Ras homolog gene family member A ( RhoA ) [18], 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 [19]. FAK1 thereby may regulate cytoskeletal dynamics by modulating activity of RASGRF1, p190RhoGAP, and their effector RhoA [1].

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 [20], [21].

The activated ROCK kinases also phosphorylate and inactivate the Myosin light chain phosphatase ( MLCP ) [22] that attenuates phosphorylation of the Myosin light chains ( MELC ) and MRLC [23] and formation of actomyosin stress fibers.


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