Nuclear FAK: a New Mode of Gene Regulation from Cellular Adhesions

다국어 초록 (Multilingual Abstract)

Focal adhesion kinase (FAK) is a protein tyrosine kinase (PTK) crucial in regulation of cell migration and prolifera-tion. In addition to its canonical roles as a cytoplasmic kinase downstream of integrin and growth factor receptor signaling, recent studies revealed new aspects of FAK action in the nucleus. Nuclear FAK promotes p53 and GATA4 degradation via ubiquitination, resulting in enhan-ced cell proliferation and reduced inflammatory responses. FAK can also serve as a co-transcriptional regulator that alters a gene transcriptional activity. These findings established a new paradigm of FAK signaling from cellular adhesions to the nucleus. Although physiological stimuli for controlling FAK nuclear localization have not been completely characterized, FAK shuttles from focal adhesions to the nucleus to directly convey extracellular signals. Interestingly, nuclear translocation of FAK becomes pro-minent in kinase-inhibited conditions such as in de-adhe-sion and pharmacological FAK inhibition, while a small fraction of nuclear FAK is observed a normal growth condition. In this review, roles of nuclear FAK in regulating transcription factors will be discussed. Furthermore, a potential use of a pharmacological FAK inhibitor to target nuclear FAK function in diseases such as inflammation will be emphasized.

참고문헌 (Reference)

1 Wang, Y, "Zyxin and paxillin proteins, focal adhesion plaque LIM domain proteins go nuclear" 1593 : 115-120, 2003

2 Ahn, S, "XIAP is essential for shear stressenhanced Tyr-576 phosphorylation of FAK" 399 : 256-261, 2010

3 Carter, R.A, "Vascular cell adhesion molecule 1 (CD106): a multifaceted regulator of joint inflammation" 44 : 985-994, 2001

4 Minami, T, "Thrombin stimulation of the vascular cell adhesion molecule-1 promoter in endothelial cells is mediated by tandem nuclear factor-kappa B and GATA motifs" 276 : 47632-47641, 2001

5 Molkentin, J.D, "The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression" 275 : 38949-38952, 2000

6 McLean, G.W, "The role of focal-adhesion kinase in cancer - a new therapeutic opportunity" 5 : 505-515, 2005

7 Inman, K.E, "The murine allantois, emerging paradigms in development of the mammalian umbilical cord and its relation to the fetus" 45 : 237-258, 2007

8 Frame, M.C, "The FERM domain: organizing the structure and function of FAK" 11 : 802-814, 2010

9 Klingbeil, C.K, "Targeting Pyk2 to beta 1-integrincontaining focal contacts rescues fibronectin-stimulated signaling and haptotactic motility defects of focal adhesion kinase-null cells" 152 : 97-110, 2001

10 Gurtner, G.C, "Targeted disruption of the murine VCAM1 gene, essential role of VCAM-1 in chorioallantoic fusion and placentation" 9 : 1-14, 1995

11 Karin, M, "TNFR signaling, ubiquitin-conjugated TRAFfic signals control stop-and-go for MAPK signaling complexes" 228 : 225-240, 2009

12 Bagi, C.M, "Sunitinib and PF-562,271 (FAK/Pyk2 inhibitor) effectively block growth and recovery of human hepatocellular carcinoma in a rat xenograft model" 8 : 856-865, 2009

13 Lietha, D, "Structural basis for the autoinhibition of focal adhesion kinase" 129 : 1177-1187, 2007

14 Cai, X, "Spatial and temporal regulation of focal adhesion kinase activity in living cells" 28 : 201-214, 2008

15 Zhao, X, "Role of kinase-independent and -dependent functions of FAK in endothelial cell survival and barrier function during embryonic development" 189 : 955-965, 2010

16 Ahmad, M, "Role of activating protein-1 in the regulation of the vascular cell adhesion molecule-1 gene expression by tumor necrosis factor-alpha" 273 : 4616-4621, 1998

17 Luo, S.W, "Regulation of heterochromatin remodelling and myogenin expression during muscle differentiation by FAK interaction with MBD2" 28 : 2568-2582, 2009

18 Ilić, D, "Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice" 377 : 539-544, 1995

19 Lim, Y, "PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility" 180 : 187-203, 2008

20 Lev, S, "Protein tyrosine kinase PYK2 involved in calcium-induced regulation of ion channel and MAP kinase functions" 376 : 737-745, 1995

21 Dong, J.M, "Paxillin nuclear-cytoplasmic localization is regulated by phosphorylation of the LD4 motif: evidence that nuclear paxillin promotes cell proliferation" 418 : 173-184, 2009

22 Lim, S.T, "PYK2 inhibition of p53 as an adaptive and intrinsic mechanism facilitating cell proliferation and survival" 285 : 1743-1753, 2010

23 Walsh, C, "Oral delivery of PND-1186 FAK inhibitor decreases spontaneous breast to lung metastasis in pre-clinical tumor models" 9 : 776-788, 2010

24 Lim, S.T., "Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression" 197 : 907-919, 2012

25 Aoto, H, "Nuclear translocation of cell adhesion kinase beta/proline-rich tyrosine kinase 2" 27 : 47-61, 2002

26 Lim, S.T, "Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation" 29 : 9-22, 2008

27 Furuta, Y, "Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK" 11 : 1989-1995, 1995

28 Cooper, J, "Merlin/NF2 functions upstream of the nuclear E3 ubiquitin ligase CRL4DCAF1 to suppress oncogenic gene expression" 4 : 6-, 2011

29 Lim, S.T, "Knock-in mutation reveals an essential role for focal adhesion kinase activity in blood vessel morphogenesis and cell motility-polarity but not cell proliferation" 285 : 21526-21536, 2010

30 Stokes, J.B, "Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment" 10 : 2135-2145, 2011

31 Libby, P., "Inflammation in atherosclerosis" 420 : 868-874, 2002

32 Libby, P, "Inflammation and atherosclerosis" 105 : 1135-1143, 2002

33 Dikic, I, "Identification of a new Pyk2 isoform implicated in chemokine and antigen receptor signaling" 273 : 14301-14308, 1998

34 Mitra, S.K, "Focal adhesion kinase, in command and control of cell motility" 6 : 56-68, 2005

35 Lim, S.-T, "FERM control of FAK function, Implications for cancer therapy" 7 : 2306-2314, 2008

36 Lawson, C, "FAK promotes recruitment of talin to nascent adhesions to control cell motility" 196 : 223-232, 2012

37 Ossovskaya, V., "FAK nuclear export signal sequences" 582 : 2402-2406, 2008

38 Mei, L, "FAK interaction with MBD2, A link from cell adhesion to nuclear chromatin remodeling" 4 : 77-80, 2010

39 Schlaepfer, D.D, "Evidence for in vivo phosphorylation of the Grb2 SH2-domain binding site on focal adhesion kinase by Src-family protein-tyrosine kinases" 16 : 5623-5633, 1996

40 Pober, J.S., "Endothelial activation, intracellular signaling pathways" 4 (4): S109-S116, 2002

41 Braren, R, "Endothelial FAK is essential for vascular network stability, cell survival, and lamellipodial formation" 172 : 151-162, 2006

42 Kobayashi, S, "Diminished GATA4 protein levels contribute to hyperglycemia-induced cardiomyocyte injury" 282 : 21945-21952, 2007

43 Kwee, L, "Defective development of the embryonic and extraembryonic circulatory systems in vascular cell adhesion molecule (VCAM-1) deficient mice" 121 : 489-503, 1995

44 Ceccarelli, D.F, "Crystal structure of the FERM domain of focal adhesion kinase" 281 : 252-259, 2006

45 Schlaepfer, D.D, "Control of motile and invasive cell phenotypes by focal adhesion kinase" 1692 : 77-102, 2004

46 Shen, T.L, "Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis" 169 : 941-952, 2005

47 Weis, S.M, "Compensatory role for Pyk2 during angiogenesis in adult mice lacking endothelial cell FAK" 181 : 43-50, 2008

48 Schaller, M.D., "Cellular functions of FAK kinases, insight into molecular mechanisms and novel functions" 123 : 1007-1013, 2010

49 Dai, Q., "CHIP activates HSF1 and confers protection against apoptosis and cellular stress" 22 : 5446-5458, 2003

50 Roberts, W.G, "Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271" 68 : 1935-1944, 2008

51 Cybulsky, M.I, "A major role for VCAM-1, but not ICAM-1, in early atherosclerosis" 107 : 1255-1262, 2001