Cytoskeleton remodeling FAK signaling
FAK signaling The biological importance of PTK2 protein tyrosine kinase 2, or Focaladhesion kinase 1 ( FAK1 )-mediated signal transduction is underscored by the factthat this tyrosine kinase plays a fundamental role in embryonic development, in controlof cell migration, cell cycle progression, and in apoptosis. Binding of ECM proteins to Integrins leads to activation ofv-Src sarcoma viral oncogene homolog ( c-Src ), thereby leading to directphosphorylation and activation of FAK1 by c-Src . FAK1 is one of the most important components in Vascularendothelial growth factor (VEGF)-induced signaling in cardiac myocytes. It plays acritical role in adhesive interactions between cardiac myocytes and ECM. VEGF-Ainduces tyrosine phosphorylation and activation of FAK1 via activation ofVEGF-receptor 2 tyrosine kinase ( VEGFR-2 ) and c-Src. G protein-coupled Bombesin receptor activation byBombesin induces rapid FAK1 phosphorylation through transformation andactivation of G-protein alpha-q/11 that stimulates Phospholipase C beta (PLC-beta )-dependent increase of the intracellular Ca(2+) concentration.Ca(2+) binding activates Calmodulin and Calcium-calmodulin kinase II (CaMKII). Activated CaMKII directly phosphorylates the recombinantCOOH-terminal region of FAK1 . FAK1 binds to the death domain kinase receptor-interactingprotein ( RIPK1 ). FAK1 provides a survival signal function by binding toRIPK1. This binding leads to inhibition of the interaction of RIPK1 withthe adapter protein TRAF3 . FAK1 plays an anti-apoptotic role in anchorage-dependent cellsvia activating the Phosphatidylinositol 3-kinase ( PI3K )/ v-AKT murine thymomaviral oncogene homolog ( AKT ) survival pathway. Phosphorylation by AKTinhibits Glycogen synthase kinase 3 beta ( GSK3-beta ) followed by activation ofCyclin D3. This pathway ultimately leads to the inhibition of the apoptosis andregulation of cell cycle . FAK1 plays a major role in regulating Breast cancer anti-estrogenresistance 1 (P130CAS ) phosphorylation. It functions as a docking or scaffoldingprotein that facilitates the recruitment of the c-Src to phosphorylateP130CAS . FAK1 promotes reorganization of cytoskeleton by activation ofsmall GTPases Rac1 and CDC42 through P130CAS/ v-CRK sarcoma virusCT10 oncogene homolog ( CRK)/ Dedicator of cytokinesis 1 ( DOCK1) andp130CAS/ CRK/ Rap guanine nucleotide exchange factor 1 ( C3G)/RAP1A member of RAS oncogene family ( RAP-1A)/ FERM RhoGEF and pleckstrin domainprotein 2 ( FARP2 ) pathways, respectively. Rac1 and CDC42 stimulatethe formation of protrusive structures such as membrane ruffles, lamellipodia andfilopodia. Another small GTPase, RhoA, regulates contractility and assembly ofactin stress fibers and focal adhesions. Integrin engagement initially inactivatesRhoA, in a c-Src -dependent manner, but has no effect on the activityof CDC42 or Rac1. Additionally, early integrin signaling inducesactivation and tyrosine phosphorylation of RhoA GTPase activating proteinp190RhoGAP via a mechanism that requires c-Src . FAK1 mediates attachment-induced activation of Mitogen-activatedprotein kinase 8 ( JNK1 ) in a Rac-dependent manner. Cell attachment leads to theactivation of the p21-Activated kinase 1 ( PAK1 )/ Mitogen-activated proteinkinase kinase kinase 1 ( MEKK1 )/ Dual specificity mitogen-activated proteinkinase kinase 7 ( MKK7 )/ JNK1 pathway . JNK1 phosphorylates Paxillin, a focal adhesionadaptor. FAK1 directly interacts with Phospholipase C gamma 1 (PLC-gamma 1 ). This leads to increase in the Inositol phosphate ( IP3 )concentration and production of Diacylglycerol ( DAG ) in fibroblasts. FAK1cannot phosphorylate PLC-gamma 1 directly. It recruits PLC-gamma 1to the plasma membrane at sites of cell-matrix adhesion, thereby promoting its enzymaticactivity and inducing its phosphorylation by the FAK1 -associated c-Src. Increased FAK1 activity in the cells contributes to thephosphorylation of Src homology 2 domain containing transforming protein ( Shc )by c-Src and likely to the promotion of the Growth factor receptor bound 2 (GRB2 )/ Son of sevenless proteins ( SOS )/ v-Ha-ras Harvey rat sarcomaviral oncogene homolog ( H-Ras )/ v-Raf-1 murine leukemia viral oncogene homolog1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 andMEK2 )/ Mitogen-activated protein kinases 1 and 3 ( ERK1/2 ) signaling,which leads to cell proliferation . ERK1/2 also directlyphosphorylates and activates proteinase Calpain 2 (m) . Calpain 2 (m) is involved in cell migration via its ability toregulate focal adhesion dynamics and rear retraction. Calpain 2 (m), but notCalpain 1, is required for proteolysis of the cytoskeletal and focal adhesion proteinsFAK1, Paxillin and Talin. It limits membrane protrusions andregulates lamellipodial dynamics at the leading edge of migrating cells . Integrin-mediated cell spreading and the formation of focal adhesionsare down-regulated by PTEN phosphatase. PTEN interacts with FAK1 andreduces the level of its tyrosine phosphorylation .