Adapter molecule crk explained

Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the CRK gene.^[1]

The CRK protein participates in the Reelin signaling cascade downstream of DAB1.^{[2] [3]}

Function

Adapter molecule crk is a member of an adapter protein family that binds to several tyrosine-phosphorylated proteins. This protein has several SH2 and SH3 domains (src-homology domains) and is involved in several signaling pathways, recruiting cytoplasmic proteins in the vicinity of tyrosine kinase through SH2-phosphotyrosine interaction. The N-terminal SH2 domain of this protein functions as a positive regulator of transformation whereas the C-terminal SH3 domain functions as a negative regulator of transformation. Two alternative transcripts encoding different isoforms with distinct biological activity have been described.^[4]

Crk together with CrkL participates in the Reelin signaling cascade downstream of DAB1.^{[2] [3]}

v-Crk, a transforming oncoprotein from avian sarcoma viruses, is a fusion of viral "gag" protein with the SH2 and SH3 domains of cellular Crk.^[5] The name Crk is from "CT10 Regulator of Kinase" where CT10 is the avian virus from which was isolated a protein, lacking kinase domains, but capable of stimulating phosphorylation of tyrosines in cells.^[6]

Crk should not be confused with Src, which also has cellular (c-Src) and viral (v-Src) forms and is involved in some of the same signaling pathways but is a protein tyrosine-kinase.

Interactions

CRK (gene) has been shown to interact with:

• BCAR1,^{[7] [8] [9] [10] [11] [12] [13] [14] [15]}
• Cbl gene,^{[16] [17]}
• Dock180,^{[9] [10] [18] [19]}
• EPS15,^[20]
• Epidermal growth factor receptor,^{[21] [22]}
• Grb2,^{[23] [24] [25]}
• IRS4,^{[26] [27]}
• MAP4K1,^{[28] [29] [30]}
• MAPK8,^[31]
• NEDD9,^{[32] [33]}
• PDGFRA,^[34]
• PDGFRB,^[35]
• PTK2,^{[9] [12]}
• Paxillin^{[12] [36]}
• RAPGEF1,^[37]
• RICS,^{[38] [39]}
• SH3KBP1,^[40] and
• SOS1.^[25]

See also

• CrkL, "Crk-like" protein

Further reading

• Feller SM, Ren R, Hanafusa H, Baltimore D . SH2 and SH3 domains as molecular adhesives: the interactions of Crk and Abl. . Trends Biochem. Sci. . 19 . 11 . 453–8 . 1995 . 7855886 . 10.1016/0968-0004(94)90129-5 .
• Feller SM, Posern G, Voss J . Physiological signals and oncogenesis mediated through Crk family adapter proteins. . J. Cell. Physiol. . 177 . 4 . 535–52 . 1999 . 10092207 . 10.1002/(SICI)1097-4652(199812)177:4<535::AID-JCP5>3.0.CO;2-E . 10190385 . etal.
• Pessin JE, Okada S . Insulin and EGF receptors integrate the Ras and Rap signaling pathways. . Endocr. J. . 46 Suppl . S11–6 . 2002 . 12054111 . 10.1507/endocrj.46.suppl_s11. free .
• Cicchetti P, Mayer BJ, Thiel G, Baltimore D . Identification of a protein that binds to the SH3 region of Abl and is similar to Bcr and GAP-rho. . Science . 257 . 5071 . 803–6 . 1992 . 1379745 . 10.1126/science.1379745 . 1992Sci...257..803C .
• Matsuda M, Tanaka S, Nagata S . Two species of human CRK cDNA encode proteins with distinct biological activities. . Mol. Cell. Biol. . 12 . 8 . 3482–9 . 1992 . 1630456 . 364597 . etal. 10.1128/MCB.12.8.3482 .
• Anderson D, Koch CA, Grey L . Binding of SH2 domains of phospholipase C gamma 1, GAP, and Src to activated growth factor receptors. . Science . 250 . 4983 . 979–82 . 1990 . 2173144 . 10.1126/science.2173144 . 1990Sci...250..979A . etal. 1807/9443 . free .
• Schaller MD, Hildebrand JD, Shannon JD . Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. . Mol. Cell. Biol. . 14 . 3 . 1680–8 . 1994 . 7509446 . 358526 . etal. 10.1128/MCB.14.3.1680 .
• Hempstead BL, Birge RB, Fajardo JE . Expression of the v-crk oncogene product in PC12 cells results in rapid differentiation by both nerve growth factor- and epidermal growth factor-dependent pathways. . Mol. Cell. Biol. . 14 . 3 . 1964–71 . 1994 . 7509449 . 358555 . etal. 10.1128/MCB.14.3.1964 .
• Tanaka S, Morishita T, Hashimoto Y . 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. U.S.A. . 91 . 8 . 3443–7 . 1994 . 7512734 . 10.1073/pnas.91.8.3443 . 43593 . 1994PNAS...91.3443T . etal. free .
• Calalb MB, Polte TR, Hanks SK . Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. . Mol. Cell. Biol. . 15 . 2 . 954–63 . 1995 . 7529876 . 231984 . 10.1128/MCB.15.2.954 .
• Teng KK, Lander H, Fajardo JE . v-Crk modulation of growth factor-induced PC12 cell differentiation involves the Src homology 2 domain of v-Crk and sustained activation of the Ras/mitogen-activated protein kinase pathway. . J. Biol. Chem. . 270 . 35 . 20677–85 . 1995 . 7657647 . 10.1074/jbc.270.35.20677 . etal. free .
• Schumacher C, Knudsen BS, Ohuchi T . The SH3 domain of Crk binds specifically to a conserved proline-rich motif in Eps15 and Eps15R. . J. Biol. Chem. . 270 . 25 . 15341–7 . 1995 . 7797522 . 10.1074/jbc.270.25.15341 . etal. free .
• Matsuda M, Hashimoto Y, Muroya K . CRK protein binds to two guanine nucleotide-releasing proteins for the Ras family and modulates nerve growth factor-induced activation of Ras in PC12 cells. . Mol. Cell. Biol. . 14 . 8 . 5495–500 . 1994 . 8035825 . 359069 . etal. 10.1128/MCB.14.8.5495 .
• Feller SM, Knudsen B, Hanafusa H . c-Abl kinase regulates the protein binding activity of c-Crk. . EMBO J. . 13 . 10 . 2341–51 . 1994 . 8194526 . 395099 . 10.1002/j.1460-2075.1994.tb06518.x .
• Fioretos T, Heisterkamp N, Groffen J . CRK proto-oncogene maps to human chromosome band 17p13. . Oncogene . 8 . 10 . 2853–5 . 1993 . 8378094 . etal.
• Smit L, van der Horst G, Borst J . Sos, Vav, and C3G participate in B cell receptor-induced signaling pathways and differentially associate with Shc-Grb2, Crk, and Crk-L adaptors. . J. Biol. Chem. . 271 . 15 . 8564–9 . 1996 . 8621483 . 10.1074/jbc.271.15.8564 . free .
• Beitner-Johnson D, Blakesley VA, Shen-Orr Z . The proto-oncogene product c-Crk associates with insulin receptor substrate-1 and 4PS. Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling. . J. Biol. Chem. . 271 . 16 . 9287–90 . 1996 . 8621590 . 10.1074/jbc.271.16.9287. etal. free .
• Hasegawa H, Kiyokawa E, Tanaka S . DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane. . Mol. Cell. Biol. . 16 . 4 . 1770–6 . 1996 . 8657152 . 231163 . etal. 10.1128/MCB.16.4.1770 .

External links

• Crk Info with links in the Cell Migration Gateway

Notes and References

1. 10.1073/pnas.87.7.2638. Mayer BJ, Hanafusa H . Association of the v-crk oncogene product with phosphotyrosine-containing proteins and protein kinase activity. . Proc Natl Acad Sci U S A . 1990 . 87 . 7 . 2638–42 . 1690891 . 53745 . 1990PNAS...87.2638M . free .
2. Matsuki T, Pramatarova A, Howell BW . Reduction of Crk and CrkL expression blocks reelin-induced dendritogenesis . J. Cell Sci. . 121 . Pt 11 . 1869–75 . June 2008. 18477607 . 2430739 . 10.1242/jcs.027334 .
3. Park TJ, Curran T . Crk and Crk-like play essential overlapping roles downstream of disabled-1 in the Reelin pathway . J. Neurosci. . 28 . 50 . 13551–62 . December 2008. 19074029 . 2628718 . 10.1523/JNEUROSCI.4323-08.2008 .
4. Web site: Entrez Gene: CRK v-crk sarcoma virus CT10 oncogene homolog (avian).
5. Direct Binding of C-terminal Region of p130Graphic to SH2 and SH3 Domains of Src Kinase . Tetsuya Nakamoto . Ryuichi Sakai . Keiya Ozawa . Yoshio Yazaki . Hisamaru Hirai . J. Biol. Chem.. 1996 . 271. 15 . 8959–8965. 10.1074/jbc.271.15.8959 . 8621540. free .
6. Mayer BJ, Hamaguchi M, Hanafusa H . A novel viral oncogene with structural similarity to phospholipase C . Nature . 332 . 6161 . 272–5 . March 1988. 2450282 . 10.1038/332272a0 . 1988Natur.332..272M . 4352676 .
7. Zhou B, Liu L, Reddivari M, Zhang XA . The palmitoylation of metastasis suppressor KAI1/CD82 is important for its motility- and invasiveness-inhibitory activity . Cancer Res. . 64 . 20 . 7455–63 . 2004 . 15492270 . 10.1158/0008-5472.CAN-04-1574 . free .
8. Di Stefano P, Cabodi S, Boeri Erba E, Margaria V, Bergatto E, Giuffrida MG, Silengo L, Tarone G, Turco E, Defilippi P . P130Cas-associated protein (p140Cap) as a new tyrosine-phosphorylated protein involved in cell spreading . Mol. Biol. Cell . 15 . 2 . 787–800 . 2004 . 14657239 . 329393 . 10.1091/mbc.E03-09-0689 .
9. Hsia DA, Mitra SK, Hauck CR, Streblow DN, Nelson JA, Ilic D, Huang S, Li E, Nemerow GR, Leng J, Spencer KS, Cheresh DA, Schlaepfer DD . Differential regulation of cell motility and invasion by FAK . J. Cell Biol. . 160 . 5 . 753–67 . 2003 . 12615911 . 2173366 . 10.1083/jcb.200212114 .
10. Gu J, Sumida Y, Sanzen N, Sekiguchi K . Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway . J. Biol. Chem. . 276 . 29 . 27090–7 . 2001 . 11369773 . 10.1074/jbc.M102284200 . free .
11. Garton AJ, Tonks NK . Regulation of fibroblast motility by the protein tyrosine phosphatase PTP-PEST . J. Biol. Chem. . 274 . 6 . 3811–8 . 1999 . 9920935 . 10.1074/jbc.274.6.3811. free .
12. Angers-Loustau A, Côté JF, Charest A, Dowbenko D, Spencer S, Lasky LA, Tremblay ML . Protein tyrosine phosphatase-PEST regulates focal adhesion disassembly, migration, and cytokinesis in fibroblasts . J. Cell Biol. . 144 . 5 . 1019–31 . 1999 . 10085298 . 2148201 . 10.1083/jcb.144.5.1019.
13. Qiu W, Cobb RR, Scholz W . Inhibition of p130cas tyrosine phosphorylation by calyculin A . J. Leukoc. Biol. . 63 . 5 . 631–5 . 1998 . 9581808 . 10.1002/jlb.63.5.631. 11177730 . free .
14. Blaukat A, Ivankovic-Dikic I, Grönroos E, Dolfi F, Tokiwa G, Vuori K, Dikic I . Adaptor proteins Grb2 and Crk couple Pyk2 with activation of specific mitogen-activated protein kinase cascades . J. Biol. Chem. . 274 . 21 . 14893–901 . 1999 . 10329689 . 10.1074/jbc.274.21.14893. free .
15. Wang JF, Park IW, Groopman JE . Stromal cell-derived factor-1alpha stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C . Blood . 95 . 8 . 2505–13 . 2000 . 10753828 . 10.1182/blood.V95.8.2505.
16. Gesbert F, Garbay C, Bertoglio J . Interleukin-2 stimulation induces tyrosine phosphorylation of p120-Cbl and CrkL and formation of multimolecular signaling complexes in T lymphocytes and natural killer cells . J. Biol. Chem. . 273 . 7 . 3986–93 . 1998 . 9461587 . 10.1074/jbc.273.7.3986. free .
17. Husson H, Mograbi B, Schmid-Antomarchi H, Fischer S, Rossi B . CSF-1 stimulation induces the formation of a multiprotein complex including CSF-1 receptor, c-Cbl, PI 3-kinase, Crk-II and Grb2 . Oncogene . 14 . 19 . 2331–8 . 1997 . 9178909 . 10.1038/sj.onc.1201074 . free .
18. Nishihara H, Kobayashi S, Hashimoto Y, Ohba F, Mochizuki N, Kurata T, Nagashima K, Matsuda M . Non-adherent cell-specific expression of DOCK2, a member of the human CDM-family proteins . Biochim. Biophys. Acta . 1452 . 2 . 179–87 . 1999 . 10559471 . 10.1016/S0167-4889(99)00133-0. free .
19. Hasegawa H, Kiyokawa E, Tanaka S, Nagashima K, Gotoh N, Shibuya M, Kurata T, Matsuda M . DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane . Mol. Cell. Biol. . 16 . 4 . 1770–6 . 1996 . 8657152 . 231163 . 10.1128/MCB.16.4.1770.
20. Schumacher C, Knudsen BS, Ohuchi T, Di Fiore PP, Glassman RH, Hanafusa H . The SH3 domain of Crk binds specifically to a conserved proline-rich motif in Eps15 and Eps15R . J. Biol. Chem. . 270 . 25 . 15341–7 . 1995 . 7797522 . 10.1074/jbc.270.25.15341. free .
21. 9614078 Schulze WX, Deng L, Mann M . Phosphotyrosine interactome of the ErbB-receptor kinase family . Mol. Syst. Biol. . 1 . 1. E1–E13 . 2005 . 16729043 . 1681463 . 10.1038/msb4100012.
22. Hashimoto Y, Katayama H, Kiyokawa E, Ota S, Kurata T, Gotoh N, Otsuka N, Shibata M, Matsuda M . Phosphorylation of CrkII adaptor protein at tyrosine 221 by epidermal growth factor receptor . J. Biol. Chem. . 273 . 27 . 17186–91 . 1998 . 9642287 . 10.1074/jbc.273.27.17186. free .
23. Riordan SM, Lidder S, Williams R, Skouteris GG . The beta-subunit of the hepatocyte growth factor/scatter factor (HGF/SF) receptor phosphorylates and associates with CrkII: expression of CrkII enhances HGF/SF-induced mitogenesis . Biochem. J. . 350 . 3. 925–32 . 2000 . 10970810 . 1221328 . 10.1042/0264-6021:3500925.
24. Matsuda M, Ota S, Tanimura R, Nakamura H, Matuoka K, Takenawa T, Nagashima K, Kurata T . Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins . J. Biol. Chem. . 271 . 24 . 14468–72 . 1996 . 8662907 . 10.1074/jbc.271.24.14468. free .
25. Okada S, Pessin JE . Interactions between Src homology (SH) 2/SH3 adapter proteins and the guanylnucleotide exchange factor SOS are differentially regulated by insulin and epidermal growth factor . J. Biol. Chem. . 271 . 41 . 25533–8 . 1996 . 8810325 . 10.1074/jbc.271.41.25533. free .
26. Karas M, Koval AP, Zick Y, LeRoith D . The insulin-like growth factor I receptor-induced interaction of insulin receptor substrate-4 and Crk-II . Endocrinology . 142 . 5 . 1835–40 . 2001 . 11316748 . 10.1210/endo.142.5.8135. free .
27. Koval AP, Karas M, Zick Y, LeRoith D . Interplay of the proto-oncogene proteins CrkL and CrkII in insulin-like growth factor-I receptor-mediated signal transduction . J. Biol. Chem. . 273 . 24 . 14780–7 . 1998 . 9614078 . 10.1074/jbc.273.24.14780. free .
28. Oehrl W, Kardinal C, Ruf S, Adermann K, Groffen J, Feng GS, Blenis J, Tan TH, Feller SM . The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are candidates for highly selective signal transducers of Crk family adapter proteins . Oncogene . 17 . 15 . 1893–901 . 1998 . 9788432 . 10.1038/sj.onc.1202108 . free .
29. Ling P, Yao Z, Meyer CF, Wang XS, Oehrl W, Feller SM, Tan TH . Interaction of hematopoietic progenitor kinase 1 with adapter proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase . Mol. Cell. Biol. . 19 . 2 . 1359–68 . 1999 . 9891069 . 116064 . 10.1128/MCB.19.2.1359.
30. Ling P, Meyer CF, Redmond LP, Shui JW, Davis B, Rich RR, Hu MC, Wange RL, Tan TH . Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling . J. Biol. Chem. . 276 . 22 . 18908–14 . 2001 . 11279207 . 10.1074/jbc.M101485200 . free .
31. Girardin SE, Yaniv M . A direct interaction between JNK1 and CrkII is critical for Rac1-induced JNK activation . EMBO J. . 20 . 13 . 3437–46 . 2001 . 11432831 . 125507 . 10.1093/emboj/20.13.3437 .
32. Minegishi M, Tachibana K, Sato T, Iwata S, Nojima Y, Morimoto C . Structure and function of Cas-L, a 105-kD Crk-associated substrate-related protein that is involved in beta 1 integrin-mediated signaling in lymphocytes . J. Exp. Med. . 184 . 4 . 1365–75 . 1996 . 8879209 . 2192828 . 10.1084/jem.184.4.1365.
33. Ohashi Y, Tachibana K, Kamiguchi K, Fujita H, Morimoto C . T cell receptor-mediated tyrosine phosphorylation of Cas-L, a 105-kDa Crk-associated substrate-related protein, and its association of Crk and C3G . J. Biol. Chem. . 273 . 11 . 6446–51 . 1998 . 9497377 . 10.1074/jbc.273.11.6446. free .
34. Yokote K, Hellman U, Ekman S, Saito Y, Rönnstrand L, Saito Y, Heldin CH, Mori S . Identification of Tyr-762 in the platelet-derived growth factor alpha-receptor as the binding site for Crk proteins . Oncogene . 16 . 10 . 1229–39 . 1998 . 9546424 . 10.1038/sj.onc.1201641 . free .
35. Matsumoto T, Yokote K, Take A, Takemoto M, Asaumi S, Hashimoto Y, Matsuda M, Saito Y, Mori S . Differential interaction of CrkII adaptor protein with platelet-derived growth factor alpha- and beta-receptors is determined by its internal tyrosine phosphorylation . Biochem. Biophys. Res. Commun. . 270 . 1 . 28–33 . 2000 . 10733900 . 10.1006/bbrc.2000.2374 .
36. Abassi YA, Vuori K . Tyrosine 221 in Crk regulates adhesion-dependent membrane localization of Crk and Rac and activation of Rac signaling . EMBO J. . 21 . 17 . 4571–82 . 2002 . 12198159 . 126186 . 10.1093/emboj/cdf446.
37. Tanaka S, Morishita T, Hashimoto Y, Hattori S, Nakamura S, Shibuya M, Matuoka K, Takenawa T, Kurata T, Nagashima K . 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. U.S.A. . 91 . 8 . 3443–7 . 1994 . 7512734 . 43593 . 10.1073/pnas.91.8.3443. 1994PNAS...91.3443T . free .
38. Zhao C, Ma H, Bossy-Wetzel E, Lipton SA, Zhang Z, Feng GS . GC-GAP, a Rho family GTPase-activating protein that interacts with signaling adapters Gab1 and Gab2 . J. Biol. Chem. . 278 . 36 . 34641–53 . 2003 . 12819203 . 10.1074/jbc.M304594200 . free .
39. Moon SY, Zang H, Zheng Y . Characterization of a brain-specific Rho GTPase-activating protein, p200RhoGAP . J. Biol. Chem. . 278 . 6 . 4151–9 . 2003 . 12454018 . 10.1074/jbc.M207789200 . free .
40. Watanabe S, Take H, Takeda K, Yu ZX, Iwata N, Kajigaya S . Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes . Biochem. Biophys. Res. Commun. . 278 . 1 . 167–74 . 2000 . 11071869 . 10.1006/bbrc.2000.3760 .