Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
Metalloprotease
G-alpha
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Transporter
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
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Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
DNA
RNA
Compound
Inorganic ion
Predicted metabolite or user's structure
Reaction
Generic receptor
GPCR
Receptors with enzyme activity
Mitochondria
EPR
Golgi
Nucleus
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Peroxisome
Cytoplasm
Extracellular

Normal process
Pathological process
Binding
Cleavage
Covalent modifications
Phosphorylation
Dephosphorylation
Transformation
Transport
Catalysis
Transcription regulation
MicroRNA binding
Competition
Influence on expression
Unspecified interactions
Pharmacological effect
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Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Cell adhesion Integrin-mediated cell adhesion and migration


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Cell adhesion Integrin-mediated cell adhesion and migration

Integrin-mediated cell adhesion and migration

Cell migration is a coordinated process that involves rapid changes in the dynamics ofactin filaments, together with the formation and disassembly of cell adhesion sites.External stimuli that control cell migration are transduced into intracellularbiochemical signals through the interactions of transmembrane integrins that bind to theextracellular matrix (ECM) proteins [1].

Integrins are heterodimeric cell surface adhesion receptors formed by twononcovalently associated subunits, alpha and beta. There are 18 alpha and 8 beta subunitsthat associate to form 24 different heterodimers [2]. Most integrinsrecognize several ECM proteins, such as Laminin 1, Fibronectin andCollagen ( types I, II and IV ), whereas alpha-5/beta-1integrin 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 recruitFocal adhesion kinase ( FAK1 ) and a cytoskeletal protein Vinculin to focalcontacts. Alpha-actinin is a cytoskeletal protein that binds to Vinculinand crosslinks Actin in actomyosin stress fibers and tethers them to focalcontacts. Phosphorylation of Alpha-actinin by FAK1 reduces thecrosslinking 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]. Arp2/3complex nucleates new Actin filaments from the sides of preexisting filaments.This interaction requires phosphorylation of the Arp2/3 complex by p21-activatedkinase 1 ( PAK1 ) that leads to polymerization of Actin [7].

Zyxin is an Alpha-actinin and stress-fiber-binding protein found inmature 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 bytyrosine-protein kinase c-Src [8] and FAK1 phosphorylation[9]. PI(4,5)P2 enhances Talin association withIntegrins and stimulates the direct transient interactions of diverse cytoskeletonactin-binding proteins Vinculin, Alpha-actinin and Wiskott-Aldrichsyndrome-like ( N-WASP ), thereby regulating Actin polymerization bystimulating the actin-nucleating activity of the Arp2/3 complex [10],[7].

Integrin clustering promotes FAK1 autophosphorylation at Tyr397, therebycreating a binding site for c-Src. Phosphorylation of FAK1 at Tyr576 andTyr577 mediated by c-Src maximizes catalytic activity of FAK1.Phosphorylation of FAK1 at Tyr925 mediated by c-Src creates a binding sitefor the Growth factor receptor-bound protein 2 ( GRB2 ), thereby leading to theactivation of the Extracellular signal-regulated kinase-1/2 ( ERK1/2 ). TheGRB2 binding can displace Paxillin from its binding sites on theFAK1, and Tyr925-phosphorylated FAK1 might be selectively released from thefocal contacts.

ERK2 phosphorylates FAK1 at Ser910 and decreases Paxillin bindingto FAK1. Within focal contacts, FAK1 - c-Src -mediatedphosphorylation of Paxillin promotes ERK2 binding. ERK2 -mediatedphosphorylation of Paxillin can facilitate FAK1 binding to Paxillinand enhance FAK1 activation. Thus, there might be a regulatory cycle in whichc-Src - and ERK2 -mediated phosphorylation of FAK1 promotes itsrelease from focal contacts and ERK2 -mediated phosphorylation of Paxillinpromotes the association of non-phosphorylated FAK1 with Paxillin at new orgrowing focal contact sites [1]. Finally, local ERK2 -mediatedphosphorylation and activation of Myosin light chain kinase ( MYLK1 ) togetherwith inactivation of PAK1 contribute to cell-matrix adhesion dynamics [11].

Active FAK1 - c-Src complex facilitates binding of the CRK-associatedsubstrate ( p130Cas ) to FAK1 and its subsequent phosphorylation byc-Src. v-Crk sarcoma virus CT10 oncogene homolog ( CRK ) binds tophosphorylated p130Cas and facilitates activation of Ras-related C3 botulinumtoxin 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 ofMyosin regulatory light chains ( MRLC ) [16] and activation of theArp2/3 complex [17].

FAK1 phosphorylates and activates the Ras protein-specific guaninenucleotide-releasing factor 1 ( RASGRF1 ), an activator of Ras homolog gene familymember A ( RhoA ) [18], whereas active c-Src in the complexwith FAK1 phosphorylates and activates GTPase-activating protein Glucocorticoidreceptor DNA binding factor 1 ( p190RhoGAP ), a RhoA inhibitory protein[19]. FAK1 thereby may regulate cytoskeletal dynamics by modulatingactivity of RASGRF1, p190RhoGAP, and their effector RhoA [1].

RhoA downstream Rho-associated kinases 1 and 2 ( ROCK ) directlyphosphorylate LIM-kinase 2 ( LIMK2 ). LIMK1 and LIMK2 phosphorylateactin-associated protein Cofilin. Cofilin exhibits actin-depolymerizingactivity followed by reorganization of the Actin cytoskeleton [20],[21].

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