Oncogenic Signaling Adaptor Proteins

Leo Y. Luo^a,
William C. Hahn^{b, c, d, e
, ,}

a.
Health Sciences and Technology Program, Harvard Medical School, Boston, MA 02115, USA
b.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
c.
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA
d.
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02215, USA
e.
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA

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Corresponding author: E-mail address: William_Hahn@dfci.harvard.edu (William C. Hahn)

摘要

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Abstract: Signal transduction pathways activated by receptor tyrosine kinases (RTK) play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we focus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes, CRKL, GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets.
- Adaptor protein /
- Cancer /
- Oncogene

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参考文献(67)

[1]	Adams, S.J., Aydin, I.T., Celebi, J.T. GAB2–a scaffolding protein in cancer Mol. Cancer Res., 10 (2012),pp. 1265-1270
[2]	Albert, M.L., Kim, J.I., Birge, R.B. αvβ5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells Nat. Cell Biol., 2 (2000),pp. 899-905
[3]	Barretina, J., Caponigro, G., Stransky, N. et al. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity Nature, 483 (2012),pp. 603-607
[4]	Bell, D., Berchuck, A., Birrer, M. et al. Integrated genomic analyses of ovarian carcinoma Nature, 474 (2011),pp. 609-615
[5]	Bentires-Alj, M., Gil, S.G., Chan, R. et al. A role for the scaffolding adapter GAB2 in breast cancer Nat. Med., 12 (2006),pp. 114-121
[6]	Birge, R.B., Kalodimos, C., Inagaki, F. et al. Crk and CrkL adaptor proteins: networks for physiological and pathological signaling Cell Commun. Signal., 7 (2009),p. 13
[7]	Boehm, J.S., Hahn, W.C. Towards systematic functional characterization of cancer genomes Nat. Rev. Genet., 12 (2011),pp. 487-498
[8]	Brown, L.A., Kalloger, S.E., Miller, M.A. et al. Amplification of 11q13 in ovarian carcinoma Genes Chromosomes Cancer, 47 (2008),pp. 481-489
[9]	Brummer, T., Schramek, D., Hayes, V.M. et al. Increased proliferation and altered growth factor dependence of human mammary epithelial cells overexpressing the Gab2 docking protein J. Biol. Chem., 281 (2006),pp. 626-637
[10]	Cabodi, S., del Pilar Camacho-Leal, M., Di Stefano, P. et al. Integrin signalling adaptors: not only figurants in the cancer story Nat. Rev. Cancer, 10 (2010),pp. 858-870
[11]	Cheung, H.W., Cowley, G.S., Weir, B.A. et al. Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer Proc. Natl. Acad. Sci. USA, 108 (2011),pp. 12372-12377
[12]	Cheung, H.W., Du, J.Y., Boehm, J.S. et al. Cancer Discov., 1 (2011),pp. 608-625
[13]	Clackson, T., Wells, J.A. A hot spot of binding energy in a hormone-receptor interface Science, 267 (1995),pp. 383-386
[14]	Desnoyers, L.R., Pai, R., Ferrando, R.E. et al. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models Oncogene, 27 (2008),pp. 85-97
[15]	Dunn, G.P., Cheung, H.W., Agarwalla, P.K. et al. Proc. Natl. Acad. Sci. USA, 111 (2014),pp. 1102-1107
[16]	Eswarakumar, V.P., Lax, I., Schlessinger, J. Cellular signaling by fibroblast growth factor receptors Cytokine Growth Factor Rev., 16 (2005),pp. 139-149
[17]	Fathers, K.E., Rodrigues, S., Zuo, D. et al. CrkII transgene induces atypical mammary gland development and tumorigenesis Am. J. Pathol., 176 (2010),pp. 446-460
[18]	Feller, S.M. Crk family adaptors-signalling complex formation and biological roles Oncogene, 20 (2001),pp. 6348-6371
[19]	Feller, S.M., Knudsen, B., Hanafusa, H. Cellular proteins binding to the first Src homology 3 (SH3) domain of the proto-oncogene product c-Crk indicate Crk-specific signaling pathways Oncogene, 10 (1995),pp. 1465-1473
[20]	Fischer, U., Keller, A., Leidinger, P. et al. A different view on DNA amplifications indicates frequent, highly complex, and stable amplicons on 12q13-21 in glioma Mol. Cancer Res., 6 (2008),pp. 576-584
[21]	Gotoh, N. Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins Cancer Sci., 99 (2008),pp. 1319-1325
[22]	Gotoh, N., Laks, S., Nakashima, M. et al. FRS2 family docking proteins with overlapping roles in activation of MAP kinase have distinct spatial-temporal patterns of expression of their transcripts FEBS Lett., 564 (2004),pp. 14-18
[23]	Gotoh, N., Manova, K., Tanaka, S. et al. The docking protein FRS2α is an essential component of multiple fibroblast growth factor responses during early mouse development Mol. Cell. Biol., 25 (2005),pp. 4105-4116
[24]	Gotoh, T., Hattori, S., Nakamura, S. et al. Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G Mol. Cell. Biol., 15 (1995),pp. 6746-6753
[25]	Gu, H., Neel, B.G. The “Gab” in signal transduction Trends Cell Biol., 13 (2003),pp. 122-130
[26]	Gu, H., Pratt, J.C., Burakoff, S.J. et al. Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation Mol. Cell, 2 (1998),pp. 729-740
[27]	Guris, D.L., Fantes, J., Tara, D. et al. Nat. Genet., 27 (2001),pp. 293-298
[28]	Heikkinen, L.S., Kazlauskas, A., Melen, K. et al. Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling J. Biol. Chem., 283 (2008),pp. 5719-5727
[29]	Horst, B., Gruvberger-Saal, S.K., Hopkins, B.D. et al. Gab2-mediated signaling promotes melanoma metastasis Am. J. Pathol., 174 (2009),pp. 1524-1533
[30]	Johannessen, C.M., Johnson, L.A., Piccioni, F. et al. A melanocyte lineage program confers resistance to MAP kinase pathway inhibition Nature, 504 (2013),pp. 138-142
[31]	Ke, Y., Wu, D., Princen, F. et al. Role of Gab2 in mammary tumorigenesis and metastasis Oncogene, 26 (2007),pp. 4951-4960
[32]	Kim, Y.H., Kwei, K.A., Girard, L. et al. Oncogene, 29 (2010),pp. 1421-1430
[33]	Kouhara, H., Hadari, Y.R., Spivak-Kroizman, T. et al. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway Cell, 89 (1997),pp. 693-702
[34]	Lamesch, P., Li, N., Milstein, S. et al. hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes Genomics, 89 (2007),pp. 307-315
[35]	Lemmon, M.A., Schlessinger, J. Cell signaling by receptor tyrosine kinases Cell, 141 (2010),pp. 1117-1134
[36]	Lock, L.S., Royal, I., Naujokas, M.A. et al. Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases J. Biol. Chem., 275 (2000),pp. 31536-31545
[37]	Luo, B., Cheung, H.W., Subramanian, A. et al. Highly parallel identification of essential genes in cancer cells Proc. Natl. Acad. Sci. USA, 105 (2008),pp. 20380-20385
[38]	Luo, L.Y., Kim, E., Cheung, H.W. et al. The tyrosine kinase adaptor protein FRS2 is oncogenic and amplified in high-grade serous ovarian cancer Mol. Cancer Res., 13 (2015),pp. 502-509
[39]	Miller, C.T., Chen, G., Gharib, T.G. et al. Increased C-CRK proto-oncogene expression is associated with an aggressive phenotype in lung adenocarcinomas Oncogene, 22 (2003),pp. 7950-7957
[40]	Moreira, I.S., Fernandes, P.A., Ramos, M.J. Hot spots–a review of the protein-protein interface determinant amino-acid residues Proteins, 68 (2007),pp. 803-812
[41]	Muller, Y.A., Li, B., Christinger, H.W. et al. Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site Proc. Natl. Acad. Sci. USA, 94 (1997),pp. 7192-7197
[42]	Nichols, G.L., Raines, M.A., Vera, J.C. et al. Identification of CRKL as the constitutively phosphorylated 39-kD tyrosine phosphoprotein in chronic myelogenous leukemia cells Blood, 84 (1994),pp. 2912-2918
[43]	Nishida, K., Hirano, T. The role of Gab family scaffolding adapter proteins in the signal transduction of cytokine and growth factor receptors Cancer Sci., 94 (2003),pp. 1029-1033
[44]	Nishihara, H., Tanaka, S., Tsuda, M. et al. Molecular and immunohistochemical analysis of signaling adaptor protein Crk in human cancers Cancer Lett., 180 (2002),pp. 55-61
[45]	Oda, T., Heaney, C., Hagopian, J.R. et al. Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia J. Biol. Chem., 269 (1994),pp. 22925-22928
[46]	Oltersdorf, T., Elmore, S.W., Shoemaker, A.R. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours Nature, 435 (2005),pp. 677-681
[47]	Park, J., Hu, Y., Murthy, T.V. et al. Building a human kinase gene repository: bioinformatics, molecular cloning, and functional validation Proc. Natl. Acad. Sci. USA, 102 (2005),pp. 8114-8119
[48]	Pawson, T., Scott, J.D. Signaling through scaffold, anchoring, and adaptor proteins Science, 278 (1997),pp. 2075-2080
[49]	Sakai, R., Nakamoto, T., Ozawa, K. et al. Characterization of the kinase activity essential for tyrosine phosphorylation of p130Cas in fibroblasts Oncogene, 14 (1997),pp. 1419-1426
[50]	Sato, T., Gotoh, N. The FRS2 family of docking/scaffolding adaptor proteins as therapeutic targets of cancer treatment Expert Opin. Ther. Targets, 13 (2009),pp. 689-700
[51]	Sattler, M., Salgia, R., Shrikhande, G. et al. Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-kit, phosphatidylinositol 3-kinase, and p120 (CBL) J. Biol. Chem., 272 (1997),pp. 10248-10253
[52]	Schonherr, C., Yang, H.L., Vigny, M. et al. Oncogene, 29 (2010),pp. 2817-2830
[53]	Schwab, M. Amplification of oncogenes in human cancer cells BioEssays, 20 (1998),pp. 473-479
[54]	Senechal, K., Halpern, J., Sawyers, C.L. The CRKL adaptor protein transforms fibroblasts and functions in transformation by the BCR-ABL oncogene J. Biol. Chem., 271 (1996),pp. 23255-23261
[55]	Seo, J.H., Wood, L.J., Agarwal, A. et al. A specific need for CRKL in p210BCR-ABL-induced transformation of mouse hematopoietic progenitors Cancer Res., 70 (2010),pp. 7325-7335
[56]	Shao, D.D., Xue, W., Krall, E.B. et al. KRAS and YAP1 converge to regulate EMT and tumor survival Cell, 158 (2014),pp. 171-184
[57]	Takino, T., Nakada, M., Miyamori, H. et al. CrkI adapter protein modulates cell migration and invasion in glioblastoma Cancer Res., 63 (2003),pp. 2335-2337
[58]	Tanaka, S., Morishita, T., Hashimoto, Y. et al. C3G, a guanine nucleotide-releasing protein expressed ubiquitously, binds to the Src homology 3 domains of CRK and GRB2/ASH proteins Proc. Natl. Acad. Sci. USA, 91 (1994),pp. 3443-3447
[59]	Thanos, C.D., DeLano, W.L., Wells, J.A. Hot-spot mimicry of a cytokine receptor by a small molecule Proc. Natl. Acad. Sci. USA, 103 (2006),pp. 15422-15427
[60]	Wang, X.K., Asmann, Y.W., Erickson-Johnson, M.R. et al. High-resolution genomic mapping reveals consistent amplification of the fibroblast growth factor receptor substrate 2 gene in well-differentiated and dedifferentiated liposarcoma Genes Chromosomes Cancer, 50 (2011),pp. 849-858
[61]	Wang, Y., Sheng, Q., Spillman, M.A. et al. Oncogene, 31 (2012),pp. 2512-2520
[62]	Weidow, C.L., Black, D.S., Bliska, J.B. et al. CAS/Crk signalling mediates uptake of Yersinia into human epithelial cells Cell. Microbiol., 2 (2000),pp. 549-560
[63]	Weir, B.A., Woo, M.S., Getz, G. et al. Characterizing the cancer genome in lung adenocarcinoma Nature, 450 (2007),pp. 893-898
[64]	Wells, J.A., McClendon, C.L. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces Nature, 450 (2007),pp. 1001-1009
[65]	Yan, K.S., Kuti, M., Yan, S. et al. FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors J. Biol. Chem., 277 (2002),pp. 17088-17094
[66]	Yang, X., Boehm, J.S., Yang, X. et al. A public genome-scale lentiviral expression library of human ORFs Nat. Methods, 8 (2011),pp. 659-661
[67]	Zhang, K., Chu, K., Wu, X. et al. Amplification of FRS2 and activation of FGFR/FRS2 signaling pathway in high-grade liposarcoma Cancer Res., 73 (2013),pp. 1298-1307