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Cytoskeleton remodeling Integrin outside-in signaling


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Cytoskeleton remodeling Integrin outside-in signaling

Integrin outside-in signaling

Integrins are heterodimeric adhesion receptors composed of alpha- andbeta-subunits. It is known that at least 18 distinct alpha subunits and 8 or more betasubunits lead to generation of 24 alpha/beta heterodimeric receptors. Most integrinsrecognize extracellular matrix (ECM) proteins, such as Laminin,Fibronectin, Vitronectin and Collagen ( types I, II and IV )[1].

Unstimulated cells are non-adherent, and cell adhesion to ECM can alter integrinavidity through intracellular signaling (inside-out signaling). Talin binding toIntegrin beta subunit triggers conformational changes of Integrins, increasingtheir affinity to the ECM proteins [2].

Cell adhesion to ECMs can activate diverse intracellular kinases, includingtyrosine-protein kinase c-Src, focal adhesion kinase FAK1 andintegrin-linked protein kinase ILK [1].

FAK1 is autophosphorylated in response to integrin activation, and/or isphosphorylated by c-Src leading to enhancement of catalytic activity ofFAK1 [3]. Integrin binding of FAK1 is not required forFAK1 localization to the focal adhesions. This may be due to the fact thatFAK1 binds to Talin and Paxillin, which interacts withIntegrins [4], [5].

A major function of integrin signaling is to link ECM proteins to intracellular actinfilaments via interactions of integrins with actin-binding proteins such as FilaminA, Talin, Alpha-actinin and ILK/ Pinch/ Parvin( alpha - and/or beta -) complex [6].

Filamin A links actin filaments in orthogonal networks or parallel bundles, andcan induce reorganization of the cytoskeleton by different pathways. Filamin Arecruits a guanine nucleotide exchange factor (GEF) TRIO, which catalyses thetransition of Filamin -bound Ras-like protein Rac1 from the GDP bound tothe the GTP form [7]. Rac1 -GTP then activates p21-activated kinase 1(PAK1). Alternatively, Filamin A directly associates with and activatedPAK1, leading to PAK-induced phosphorylation of Filamin A [8]. PAK1 also promotes activation of Actin polymerization byphosphorylating of Arp2/3 (complex of actin-related proteins) [9],[10].

Talin is also important for the linkage of integrins to the cytoskeleton. Uponintegrin clustering Talin is recruited to focal complexes where it binds andactivates phosphatidylinositol phosphate kinase type 1 gamma ( PIPKI gamma ), thatleads to the production of phosphatidylinositol-4,5-bisphosphate ( PtdIns(4,5)P2 )[11]. PtdIns(4,5)P2 binds to Talin and increases itsinteraction with Integrin. PtdIns(4,5)P2 also binds to Vinculin,which then interacts with Talin. PtdIns(4,5)P2 -bound Vinculin isreplaced by Actin filaments. PtdIns(4,5)P2 -associated vinculin cantransiently bind to the Arp2/3 complex, which nucleates Actinpolymerization. This interaction also requires Rac1 activation leading toArp2/3 phosphorylation by PAK1 [12].

Alpha-actinin connects actin fibrils to the cytoplasmic tail ofintegrins and crosslinks actin filaments to actin bundles and networks.PtdIns(4,5)P2 binding to Alpha-actinin increases its interaction withActin [13]. Phosphorylation of Alpha-actinin by FAK1decreases its associating with Actin. Alpha-actinin can also connect toActin filaments via its interaction with Vinculin [14].

ILK binds to beta Integrin subunits and phosphorylates AKT(PKB)kinase, leading to integrin-mediated cell proliferation and survival. Another ILKtarget is GSK-3 beta, whose phosphorylation leads to stabilization and increaseof Beta-catenin in nucleus where it associates with transcription factorsTcf/Lef-1 to activate gene expression including c-Myc and Cyclin D1[15].

ILK was shown to bind adapter protein PINCH which interacts with adapterprotein NCK2(Grb4) [16], [17], [18].NCK2(Grb4) can recruit PAK1 and WASP (Wiskott-Aldrich Sydromeprotein) interacting protein WIRE, leading to Arp2/3 activation andActin polymerization [19], [6]. 

Cell adhesion to extracellular matrix also regulates cell proliferation and survival.Integrin activation by Fibronectin induces phosphorylation of FAK1 andPaxillin and causes the formation of FAK1/ GRB-2/ SOScomplexes, leading to H-Ras/ c-Raf-1/ MEK1, MEK2/ Erk(MAPK1/3) activation [20].

ILK can recruit a family of F-actin binding proteins includingAlpha-parvin and Beta-parvin. Formation of ILK/ PINCH/Parvin complex is essential but not sufficient for cell adhesion [6].Paxillin is an additional interactor, which binds Integrins, ILK,Alpha-parvin to focal adhesions via interaction with Vinculin [21].