Cytoskeleton remodeling - FAK signaling

FAK signaling

The biological importance of PTK2 protein tyrosine kinase 2, or Focal adhesion kinase 1 (FAK1)-mediated signal transduction is underscored by the fact that this tyrosine kinase plays a fundamental role in embryonic development, in control of cell migration, cell cycle progression, and in apoptosis.

Binding of ECM proteins to Integrins leads to activation of v-Src sarcoma viral oncogene homolog (c-Src), thereby leading to direct phosphorylation and activation of FAK1 by c-Src [1].

FAK1 is one of the most important components in Vascular endothelial growth factor (VEGF)-induced signaling in cardiac myocytes. It plays a critical role in adhesive interactions between cardiac myocytes and ECM. VEGF-A induces tyrosine phosphorylation and activation of FAK1 via activation of VEGF-receptor 2 tyrosine kinase (VEGFR-2) and c-Src.

G protein-coupled Bombesin receptor activation by Bombesin induces rapid FAK1 phosphorylation through transformation and activation 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 recombinant COOH-terminal region of FAK1 [2].

FAK1 binds to the death domain kinase receptor-interacting protein (RIPK1). FAK1 provides a survival signal function by binding to RIPK1. This binding leads to inhibition of the interaction of RIPK1 with the adapter protein TRAF3 [3].

FAK1 plays an anti-apoptotic role in anchorage-dependent cells via activating the Phosphatidylinositol 3-kinase (PI3K)/ v-AKT murine thymoma viral oncogene homolog (AKT) survival pathway. Phosphorylation by AKT inhibits Glycogen synthase kinase 3 beta (GSK3-beta) followed by activation of Cyclin D3. This pathway ultimately leads to the inhibition of the apoptosis and regulation of cell cycle [4].

FAK1 plays a major role in regulating Breast cancer anti-estrogen resistance 1 (P130CAS) phosphorylation. It functions as a docking or scaffolding protein that facilitates the recruitment of the c-Src to phosphorylate P130CAS [5].

FAK1 promotes reorganization of cytoskeleton by activation of small GTPases Rac1 and CDC42 through P130CAS/ v-CRK sarcoma virus CT10 oncogene homolog (CRK)/ Dedicator of cytokinesis 1 (DOCK1) and p130CAS/ CRK/ Rap guanine nucleotide exchange factor 1 (C3G)/ RAP1A member of RAS oncogene family (RAP-1A)/ FERM RhoGEF and pleckstrin domain protein 2 (FARP2) pathways, respectively. Rac1 and CDC42 stimulate the formation of protrusive structures such as membrane ruffles, lamellipodia and filopodia. Another small GTPase, RhoA, regulates contractility and assembly of actin stress fibers and focal adhesions. Integrin engagement initially inactivates RhoA, in a c-Src-dependent manner, but has no effect on the activity of CDC42 or Rac1. Additionally, early integrin signaling induces activation and tyrosine phosphorylation of RhoA GTPase activating protein p190RhoGAP via a mechanism that requires c-Src [6].

FAK1 mediates attachment-induced activation of Mitogen-activated protein kinase 8 (JNK1) in a Rac-dependent manner. Cell attachment leads to the activation of the p21-Activated kinase 1 (PAK1)/ Mitogen-activated protein kinase kinase kinase 1 (MEKK1)/ Dual specificity mitogen-activated protein kinase kinase 7 (MKK7)/ JNK1 pathway [7].

JNK1 phosphorylates Paxillin, a focal adhesion adaptor.

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. FAK1 cannot phosphorylate PLC-gamma 1 directly. It recruits PLC-gamma 1 to the plasma membrane at sites of cell-matrix adhesion, thereby promoting its enzymatic activity and inducing its phosphorylation by the FAK1-associated c-Src.

Increased FAK1 activity in the cells contributes to the phosphorylation 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 sarcoma viral oncogene homolog (H-Ras)/ v-Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2)/ Mitogen-activated protein kinases 1 and 3 (ERK1/2) signaling, which leads to cell proliferation [8]. ERK1/2 also directly phosphorylates and activates proteinase Calpain 2 (m) [9].

Calpain 2 (m) is involved in cell migration via its ability to regulate focal adhesion dynamics and rear retraction. Calpain 2 (m), but not Calpain 1, is required for proteolysis of the cytoskeletal and focal adhesion proteins FAK1, Paxillin and Talin. It limits membrane protrusions and regulates lamellipodial dynamics at the leading edge of migrating cells [10].

Integrin-mediated cell spreading and the formation of focal adhesions are down-regulated by PTEN phosphatase. PTEN interacts with FAK1 and reduces the level of its tyrosine phosphorylation [11].

References:

1. Playford MP, Schaller MD
   The interplay between Src and integrins in normal and tumor biology. Oncogene 2004 Oct 18;23(48):7928-46
2. Fan RS, Jacamo RO, Jiang X, Sinnett-Smith J, Rozengurt E
   G protein-coupled receptor activation rapidly stimulates focal adhesion kinase phosphorylation at Ser-843. Mediation by Ca2+, calmodulin, and Ca2+/calmodulin-dependent kinase II. The Journal of biological chemistry 2005 Jun 24;280(25):24212-20
3. Kurenova E, Xu LH, Yang X, Baldwin AS Jr, Craven RJ, Hanks SK, Liu ZG, Cance WG
   Focal adhesion kinase suppresses apoptosis by binding to the death domain of receptor-interacting protein. Molecular and cellular biology 2004 May;24(10):4361-71
4. Sonoda Y, Matsumoto Y, Funakoshi M, Yamamoto D, Hanks SK, Kasahara T
   Anti-apoptotic role of focal adhesion kinase (FAK). Induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of FAK in a human leukemic cell line, HL-60. The Journal of biological chemistry 2000 May 26;275(21):16309-15
5. Wei L, Yang Y, Zhang X, Yu Q
   Cleavage of p130Cas in anoikis. Journal of cellular biochemistry 2004 Feb 1;91(2):325-35
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7. Abassi YA, Vuori K
   Tyrosine 221 in Crk regulates adhesion-dependent membrane localization of Crk and Rac and activation of Rac signaling. The EMBO journal 2002 Sep 2;21(17):4571-82
8. Wang JG, Miyazu M, Xiang P, Li SN, Sokabe M, Naruse K
   Stretch-induced cell proliferation is mediated by FAK-MAPK pathway. Life sciences 2005 Apr 29;76(24):2817-25
9. Glading A, Bodnar RJ, Reynolds IJ, Shiraha H, Satish L, Potter DA, Blair HC, Wells A
   Epidermal growth factor activates m-calpain (calpain II), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation. Molecular and cellular biology 2004 Mar;24(6):2499-512
10. Franco S, Perrin B, Huttenlocher A
    Isoform specific function of calpain 2 in regulating membrane protrusion. Experimental cell research 2004 Sep 10;299(1):179-87
11. Zhang L, Yu Q, He J, Zha X
    Study of the PTEN gene expression and FAK phosphorylation in human hepatocarcinoma tissues and cell lines. Molecular and cellular biochemistry 2004 Jul;262(1-2):25-33