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Focal adhesion kinase 1

Definition:

Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Phosphorylates NEDD9 following integrin stimulation. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.; [Isoform 6]: Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.

References:

[1]. Hong Xia, et al. Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. J Biol Chem. 2004 Jul 30;279(31):33024-34. [Content Brief]

[2]. Vita M Golubovskaya, et al. Focal adhesion kinase and cancer. Histol Histopathol. 2009 Apr;24(4):503-10. [Content Brief]

[3]. Ssang-Taek Lim, et al. FERM control of FAK function: implications for cancer therapy. Cell Cycle. 2008 Aug;7(15):2306-14. [Content Brief]

[4]. Mahendra K Singh, et al. A novel Cas family member, HEPL, regulates FAK and cell spreading. Mol Biol Cell. 2008 Apr;19(4):1627-36. [Content Brief]

[5]. Satyajit K Mitra, et al. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. 2006 Oct;18(5):516-23. [Content Brief]

[6]. Jill K Slack-Davis, et al. Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007 May 18;282(20):14845-52. [Content Brief]

[7]. Kavita Vadali, et al. Focal adhesion kinase: an essential kinase in the regulation of cardiovascular functions. IUBMB Life. 2007 Nov;59(11):709-16. [Content Brief]

[8]. Ssang-Taek Lim, et al. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell. 2008 Jan 18;29(1):9-22. [Content Brief]

[9]. Ellen J Ezratty, et al. Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase. Nat Cell Biol. 2005 Jun;7(6):581-90. [Content Brief]

[10]. H Miao, et al. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol. 2000 Feb;2(2):62-9. [Content Brief]

[11]. Michael D Schaller, et al. Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. J Cell Sci. 2010 Apr 1;123(Pt 7):1007-13. [Content Brief]

[12]. R Chen, et al. Regulation of the PH-domain-containing tyrosine kinase Etk by focal adhesion kinase through the FERM domain. Nat Cell Biol. 2001 May;3(5):439-44. [Content Brief]

[13]. Jyotsnabaran Halder, et al. Therapeutic efficacy of a novel focal adhesion kinase inhibitor TAE226 in ovarian carcinoma. Cancer Res. 2007 Nov 15;67(22):10976-83. [Content Brief]

[14]. Noha Semaan, et al. Etk/BMX, a Btk family tyrosine kinase, and Mal contribute to the cross-talk between MyD88 and FAK pathways. J Immunol. 2008 Mar 1;180(5):3485-91. [Content Brief]

[15]. Silvia Continolo, et al. The proto-oncogene Fgr regulates cell migration and this requires its plasma membrane localization. Exp Cell Res. 2005 Jan 15;302(2):253-69. [Content Brief]

[16]. Yuliya Pylayeva, et al. Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. J Clin Invest. 2009 Feb;119(2):252-66. [Content Brief]

[17]. Guo-qiang Cai, et al. Downregulation of FAK-related non-kinase mediates the migratory phenotype of human fibrotic lung fibroblasts. Exp Cell Res. 2010 May 15;316(9):1600-9. [Content Brief]

[18]. Sanjay Sachdev, et al. Paxillin-Y118 phosphorylation contributes to the control of Src-induced anchorage-independent growth by FAK and adhesion. BMC Cancer. 2009 Jan 12;9:12. [Content Brief]

[19]. Roman M Salasznyk, et al. Activation of FAK is necessary for the osteogenic differentiation of human mesenchymal stem cells on laminin-5. J Cell Biochem. 2007 Feb 1;100(2):499-514. [Content Brief]

[20]. Haihao Sun, et al. Bioluminescent imaging study: FAK inhibitor, PF-562,271, preclinical study in PC3M-luc-C6 local implant and metastasis xenograft models. Cancer Biol Ther. 2010 Jul 1;10(1):38-43. [Content Brief]

[21]. Ta-Jen Liu, et al. Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol Cancer Ther. 2007 Apr;6(4):1357-67. [Content Brief]

[22]. Iván Plaza-Menacho, et al. Focal adhesion kinase (FAK) binds RET kinase via its FERM domain, priming a direct and reciprocal RET-FAK transactivation mechanism. J Biol Chem. 2011 May 13;286(19):17292-302. [Content Brief]

[23]. Timothy P Hecker, et al. Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples. Cancer Res. 2002 May 1;62(9):2699-707. [Content Brief]

[24]. Liisa J Sundberg-Smith, et al. The LIM protein leupaxin is enriched in smooth muscle and functions as an serum response factor cofactor to induce smooth muscle cell gene transcription. Circ Res. 2008 Jun 20;102(12):1502-11. [Content Brief]

[25]. K Tachibana, et al. Tyrosine phosphorylation of Crk-associated substrates by focal adhesion kinase. A putative mechanism for the integrin-mediated tyrosine phosphorylation of Crk-associated substrates. J Biol Chem. 1997 Nov 14;272(46):29083-90. [Content Brief]

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