Pathway maps

Cytoskeleton remodeling_Fibronectin-binding integrins in cell motility
Cytoskeleton remodeling_Fibronectin-binding integrins in cell motility

Object List (links open in MetaCore):

ITGA5, RhoA, Cofilin, Fibronectin, alpha-5/beta-1 integrin, ROCK, CDC42, c-Src, Rac1, Fyn, PI3K cat class IA, N-WASP, Arp2/3, ITGAV, LIMK1, PAK1, PtdIns(3,4,5)P3, VAV-1, FAK1, Talin,, PtdIns(4,5)P2, Vinculin, p190RhoGAP, Caveolin-1, IRAS, Alpha-actinin, Actin cytoskeletal, LIMK2, PI3K reg class IA (p85), alpha-V/beta-3 integrin


Fibronectin-binding integrins in cell motility

Fibronectin -binding integrins such as alpha-5/beta-1 and alpha-V/beta-3 can promote different aspects of cell migration. Adhesion to fibronectin by alpha-V/beta-3 integrins supports persistent migration, whereas alpha-5/beta-1 integrins promote random migration [1].

Integrin clustering induces focal adhesion kinase ( FAK1 ) autophosphorylation, which creates a binding site for the proto-oncogene tyrosine-protein kinase Src ( c-Src ). c-Src -mediated phosphorylation of FAK1 promotes its maximal catalytic activity. The integrin -binding protein talin recruits FAK1 and vinculin to focal contacts. Alpha-actinin is a cytoskeletal protein that binds to vinculin and crosslinks actin in actomyosin stress fibres and tethers them to the focal contacts. Phosphorylation of alpha-actinin by FAK1 reduces the crosslinking of stress fibres and prevents the maturation of focal contacts [2]. Vinculin transiently recruits the actin-related protein complex Arp2/3 to new sites of integrin aggregation [3]. Arp2/3 complex nucleates new actin filaments from the sides of preexisting filaments. This interaction requires phosphorylation of Arp2/3 complex by PAK1 (p21-activated kinase 1), which promotes actin polymerization [4], [5].

FAK1 plays a key role in the control of focal adhesion dynamics and cell migration under the regulation of small GTPases of Rho family ( Rac1, Cdc42 and Rho -A ) [6], [2]. RhoA downstream effector ROCK (protein Rho-associated kinase) directly phosphorylates LIMK1 and LIMK2 (LIM-kinases), which in turn phosphorylate cofilin (actin-associated protein). Cofilin exhibits actin -depolymerizing activity followed by reorganization of the actin cytoskeleton [7].

Activity of LIMK1 is also regulated by PAK1, the downstream effector of Rac1 and Cdc42 [8]. Cdc42 effector N-WASP (a homolog to the Wiskott-Aldrich syndrome protein) [9] regulates actin polymerization by stimulating the actin -nucleating activity of the Arp2/3 complex [5].

The Arp2/3 complex and cofilin are involved in the generation of propulsive force at the leading edge: the severing activity of cofilin and the branching activity of Arp2/3 act in synergy to drive the extension of lamellipodia. Cofilin is also required for the maintenance of a polarized cytoskeleton and thus for directional cell migration [1].

It was shown that the persistent mode of migration of cells bound to fibronectin by alpha-V/beta-3 integrins is associated with relatively high levels of cofilin activity and low levels of RhoA activity. Adhesion by alpha-5/beta-1 instead stimulates an increase in RhoA -mediated phosphorylation of cofilin and supports random cell migration [1].

Integrin signaling is mediated by distinct and separable interactions of the integrin beta tails. c-Src was shown to bind constitutively and selectively to beta3 integrins [10]. c-Src could, in turn, phosphorylate and stimulate GTPase-activating protein (GAP) p190 RhoGAP. The GAP activity of RhoGAP is specific for RhoA inhibition [11].

Vav1, a guanine nucleotide exchange factor for Rac1, Cdc42 and Rho-A, that stimulates the exchange of bound GDP for GTP, was shown to stimulate preferentially Rac1 and RhoA under integrin alpha-v/beta-3 -mediated adhesion of hematopoietic cells, but this effect was investigated on vitronectin substrate [12].

Tyrosine kinase Fyn could phosphorylate and activate Vav1 [13]. Caveolin-1 was shown to function as a membrane adaptor to link the integrin alpha-5 or alpha-v subunit to the Fyn [14]. Vav1 activity is directly controlled by substrates and products of phosphatidylinositol 3-kinase ( PI3K ). Phosphatidylinositol-4,5-bisphosphate ( PI(4,5)P2 ) inhibits activation of Vav1, whereas the product phosphatidylinositol-3,4,5-trisphosphate ( PI(3,4,5)P3 ) enhances phosphorylation and activation of Vav1 [15]. FAK1 activation may lead to its association with the regulatory subunit of PI3K ( PI3K reg p85 ), which can subsequently activate PI3K during cell adhesion [16], [17]. PI3K reg p85 could also associate with Vav1 in some types of cells [18].

The protein Nischarin was found to bind preferentially to the cytoplasmic tail of the integrin alpha-5 subunit and to inhibit cell migration [19]. Nischarin was not found in focal adhesion sites, suggesting that it binds to integrins when they are not ligated by the proteins of the extracellular matrix. Once the integrins enter into adhesion sites, Nischarin is released, allowing it to bind to the activated PAK1. This binding is enhanced by active Rac1. Interaction with Nischarin strongly inhibits the ability of PAK1 to phosphorylate substrates and this effect closely parallels Nischarin's ability to inhibit cell motility [20], [21].


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    Phosphotyrosine (p-Tyr)-dependent and -independent mechanisms of p190 RhoGAP-p120 RasGAP interaction: Tyr 1105 of p190, a substrate for c-Src, is the sole p-Tyr mediator of complex formation. Molecular and cellular biology 1998 Dec;18(12):7052-63
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    Beta3 tyrosine phosphorylation and alphavbeta3-mediated adhesion are required for Vav1 association and Rho activation in leukocytes. The Journal of biological chemistry 2005 Apr 15;280(15):15422-9
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    Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells. The Journal of biological chemistry 1998 Nov 27;273(48):31932-8
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    A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growth. Cell 1998 Sep 4;94(5):625-34
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    Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase. The Journal of biological chemistry 1996 Oct 18;271(42):26329-34
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    Differential regulation of cell migration and cell cycle progression by FAK complexes with Src, PI3K, Grb7 and Grb2 in focal contacts. FEBS letters 2001 Jun 15;499(1-2):176-81
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    Signaling through CD19 activates Vav/mitogen-activated protein kinase pathway and induces formation of a CD19/Vav/phosphatidylinositol 3-kinase complex in human B cell precursors. The Journal of biological chemistry 1994 Dec 23;269(51):32514-21
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    Nischarin, a novel protein that interacts with the integrin alpha5 subunit and inhibits cell migration. The Journal of cell biology 2000 Dec 11;151(6):1141-54
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