Focal adhesion kinase, a novel target for cancer therapy

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1 Chinese Bulletin of Life Sciences Vol. 23, No. 1 Jan., 2011 (1 ; ) (focal adhesion kinase, FAK) FAK FAK FAK FAK R34 R A Focal adhesion kinase, a novel target for cancer therapy ZHANG Wen-Jing 1, HUANG Qi-Lai 1 *, HUA Zi-Chun 1, 2 * (1Faculty of Chinese Medicine and Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China; 2The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing , China) Abstract: Focal adhesion kinase (FAK), a cytoplasmic non-receptor protein tyrosine kinase, serves as both a molecular scaffold and a mediator participating in multiple signal transduction pathways. FAK is involved in tumor cell survival, proliferation, migration and metastasis. Currently, FAK has been regarded as a potential target for cancer therapy. This review is to summarize the relationship between FAK and tumor progression, and to discuss the strategies targeting FAK for cancer treatment. Key words: focal adhesion kinase; antitumor; treatment (focal adhesion kinase, FAK) FAK 1992 v-src FAK FAK FAK [1] FAK FAK FAK (071/2009/A3 091/ 2009/A) FAK zchua@nju.edu.cn ( ) qlhuang@must.edu.mo

2 8 FAT X FAK 8q24 FAK k FAK (paxillin) (talin) 90% LD2 LD4 FAT [2] FAK Src SH2 SH3 N- FERM [7-10] (PR1 PR2 PR3) C- (focal adhesion target FAT) 6 Y397 Y407 Y576 Y577 Y861 Y925( 1) FAT 1 3 FAT C FAK FRNK FAK FRNK [11] FRNK FRNK FAK [ 1 2 F A K ] FRNK MAPK FAK FAK FIP200 [13] FAK [14] FAK SOCS FAK FERM 300 FAK Y FERM F A K E GF R Y397 PDGFR FAK FERM β FAK Y397 FAK FERM Src SH2 Src FERM FAK S r c [15] FERM FAK Tyr576/577 FAK FERM FAK paxillin p130cas FAK-Src Src FAK paxillin p130cas Crk FERM p53 SH2 G FAK Rac-1 cdc42 JNK [16] FERM F1 p53 F2 Src Tyr407 p53 F3 Mdm-2 Tyr861 Tyr925 p53 [3] N- PR1 SH2 ( Grb2) [17] SH3 Src Grb2 SH2 SH3 C PR2 PR3 FAK SH3 Ras SOS p 13 0C as Ras FAK Graf(Rho-A GTPase Ras/MAPK Y397 FAK) ASAP1(ARF-GAP SH2 Shc SH3 ANK PH ) [4-6] FAK PLCγ PI3K 85 Grb7 [18-20] C FAT FAT FAK Src FAK 15.5 k FAT FAK

3 9 [21] FAK FAK FAK FAK [34] FAK FAK FAK FAK FAK FAK FAK [22] FAK FAK FAK FAK FIP200 Ueda [35] FAK ERK [23,24] PKC/PI3K [25] Cyclin D1 Cyclin D3 mrna Pyk2 FIP200 FAK p130 CAS PI3K FAK [26] FAK p130 CAS p130 CAS FIP200 FAK FAK FIP200 FAK [27,28] Y397 FAK FAK FIP200 FAK [29] FAK F AK FIP200 FAK Pyk2 FAK Pyk2 FIP200 FAK FRNK FAK [30,31] [36] FAK FAK C- FRNK [37] FAK-Src FAK FAK -/- FRNK FAK FAK FRNK [2] FRNK FAK FRNK v-src [32] FAK NIH 3T3 FRNK FAK C D 2 B16-F10 FAK Y397 FRNK 50% [33] FAK FRNK (CD2-FAK) MDCK FAK FRNK MTLn3

4 1 0 FAK Y397 FAK Pyk2 FRNK 60% FRNK H460 FAT FAK U251MG FAK PF [38] FAT FAK LN-401 TAE226 ATP [39] [44] FAT FAK FAK F A K FAK FAT TAE226 - [45] TAE [4 0] MiaPaCa-2 FAK TAE226 RNA (sirna) FAK [42] AU-565 HA FRNK AU- FAK 565 FAK FAK ( sirna) FAK AU-565 FRNK FAT FIP200 FAK sirna FAK FRNK FAK FAK B16F10 FAK FAK FAK sirna FRNK sirna FAK DNA [1] Hao H, Naomoto Y, Bao X, et al. Focal adhesion kinase as FAK PF PF NVP-226 ATP PF TAE226 TAE226 [41] FAK FAK FAK AU-565 sirna FAK [ 43 ] [2] potential target for cancer therapy (Review). Oncol Rep, 2009, 22 (5): van Nimwegen MJ, van de Water B. Focal adhesion kinase: a potential target in cancer therapy. Biochem Pharmacol, 2007, 73 (5): FAK [3] Lim ST, Mikolon D, Stupack DG, et al. FERM control of FAK function: implications for cancer therapy. Cell Cycle, 2008, 7 (15): [4] Harte MT, Hildebrand JD, Burnham MR, et al. p130cas, a FAK paxillin substrate associated with v-src and v-crk, localizes to focal adhesions and binds to focal adhesion kinase. J Biol Chem, FAK 1996, 271 (23): [5] Liu Y, Loijens JC, Martin KH, et al. The association of FERM PF ASAP1, an ADP ribosylation factor-gtpase activating

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