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Gene Review

CRK  -  v-crk avian sarcoma virus CT10 oncogene...

Homo sapiens

Synonyms: Adapter molecule crk, CRKII, Proto-oncogene c-Crk, p38
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Disease relevance of CRK


High impact information on CRK

  • These results suggest that the conformational state of P38, controlled by Fpr4, is important for methylation of H3K36 by Set2 [5].
  • Blocking MAPKs also increased channel open probability of BK in IC and thereby it may affect K backflux and net K absorption Thus, modulation of ERK and P38 MAPK activity is involved in controlling net K secretion in the distal nephron [6].
  • CRK protein, together with GRB2/ASH and Nck proteins, belongs to the adaptor-type Src homology (SH)2-containing molecules, which transduce signals from tyrosine kinases [1].
  • The mRNAs of both the C3G and CRK proteins are expressed ubiquitously in human adult and fetal tissues [1].
  • Erythropoietin and interleukin-3 activate tyrosine phosphorylation of CBL and association with CRK adaptor proteins [7].

Chemical compound and disease context of CRK


Biological context of CRK

  • This leads to increased phosphorylation of CRK and CRKL, inhibiting these cytoskeletal regulators by promoting intramolecular over intermolecular associations [9].
  • In primary neutrophils from patients with CML, the major novel tyrosine-phosphorylated protein is CRKL, an SH2-SH3-SH3 linker protein which has an overall homology of 60% to CRK, the human homologue of the v-crk oncogene product [10].
  • The consensus sequence of the CRK SH3 binding sites as deduced from their amino acid sequences was Pro+3-Pro+2-X+1-Leu0-Pro-1-X-2-Lys-3 [11].
  • Investigation of mechanism(s) responsible for the NK action showed that NK SN inhibited TNF-alpha-mediated activation of HIV-long-terminal repeat (LTR), and upregulated the expression of signal transducer and activator of transcription (STAT)-1 and phosphorylated P38 mitogen-activated protein kinase (MAPK) [2].
  • Two distinct human CRK cDNAs, designated CRK-I and CRK-II, were isolated from human embryonic lung cells by polymerase chain reaction and by screening of a human placenta cDNA library, respectively [12].

Anatomical context of CRK

  • DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane [13].
  • Overexpression of wild-type CRK proteins CRK-I and CRK-II enhanced the nerve growth factor (NGF)-induced activation of Ras in PC12 cells, although the basal level of GTP-bound active Ras was not altered [14].
  • Differential requirements for ERK1/2 and P38 MAPK activation by thrombin in T cells. Role of P59Fyn and PKCepsilon [15].
  • Using the specific P38 inhibitor, SB203580 we found that blockade of P38 MAP kinase significantly enhanced proliferation of the pancreatic cancer cell line, PANC-1 cell, in a concentration-dependent manner [16].
  • JNK translocated from the cytosol to the nucleus upon irradiation, while P38 remained in the cytosol even after UV irradiation [17].

Associations of CRK with chemical compounds

  • The 135- to 145-kDa protein is C3G, a CRK SH3-binding guanine nucleotide exchange protein [13].
  • Inversely, in IC1LC131, Erk and Akt pathways remained active, while Jnk and P38 pathways were inhibited by gefitinib [18].
  • In contrast, the SNP-stimulated COX-2 expression was significantly reduced by either the Erk1/2 inhibitor PD-98059 or the P38 inhibitor SB-203580 and was abolished by combination of the two kinase inhibitors [19].
  • Specific inhibitors of Erk-1/2 (2'-amino-3'-methoxyflavone, PD98059) and P38 MAPK (pyridinylimidazole, SB203580) were found to suppress the uPA expression and the uPA promoter activity [20].
  • Simultaneous blocking of ERK and P38 completely abolished the effect of H(2)O(2) on c-Src expression in mouse collecting duct cells [21].

Physical interactions of CRK

  • The SH2 domain of CRK bound to the SHC protein phosphorylated on tyrosine residues by NGF stimulation [14].

Regulatory relationships of CRK

  • Phosphorylation of residues in the N-terminus of paxillin by these kinases permits the regulated recruitment of downstream effector molecules such as CRK, which (via association with CAS) is important for transduction of external signals into changes in cell motility and for modulation of gene expression by the various MAP kinase cascades [22].
  • In contrast, P38 kinase was activated by 270-280 nm light with a peak at 1 min after irradiation. c-Jun N-terminal kinase activation was observed in a narrow range of UV light with a sharp peak at 280 nm occurring in 10 min [17].

Other interactions of CRK

  • The result suggests that the amino acid at position +1 also contributes to the high affinity binding of the peptides to the SH3 domain of Grb2, but not to that of CRK [11].
  • The interaction of the CRK SH3 domain with the DOCK180 peptide was examined with an optical biosensor, based on the principles of surface plasmon resonance [11].
  • The resulting list consisted of major parts of the cAMP-protein kinase A pathway linking to ERK, P38, and AKT [23].
  • PMA had no significant effect on JNK and P38 activation, in either vector- or MLK 3-expressing cells [24].
  • From these results, we conclude that a MEK/ERK and P38 MAP kinase interaction is important for pancreatic cancer cell proliferation [16].

Analytical, diagnostic and therapeutic context of CRK


  1. C3G, a guanine nucleotide-releasing protein expressed ubiquitously, binds to the Src homology 3 domains of CRK and GRB2/ASH proteins. Tanaka, S., Morishita, T., Hashimoto, Y., Hattori, S., Nakamura, S., Shibuya, M., Matuoka, K., Takenawa, T., Kurata, T., Nagashima, K. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  2. Natural killer cell inhibits human immunodeficiency virus replication in chronically infected immune cells. Zhang, T., Li, Y., Wang, Y.J., Wang, X., Young, M., Douglas, S.D., Ho, W.Z. Antiviral Res. (2007) [Pubmed]
  3. Increased C-CRK proto-oncogene expression is associated with an aggressive phenotype in lung adenocarcinomas. Miller, C.T., Chen, G., Gharib, T.G., Wang, H., Thomas, D.G., Misek, D.E., Giordano, T.J., Yee, J., Orringer, M.B., Hanash, S.M., Beer, D.G. Oncogene (2003) [Pubmed]
  4. CRK proto-oncogene maps to human chromosome band 17p13. Fioretos, T., Heisterkamp, N., Groffen, J., Benjes, S., Morris, C. Oncogene (1993) [Pubmed]
  5. Proline isomerization of histone h3 regulates lysine methylation and gene expression. Nelson, C.J., Santos-Rosa, H., Kouzarides, T. Cell (2006) [Pubmed]
  6. Inhibition of MAPK stimulates the Ca2+-dependent big-conductance K channels in cortical collecting duct. Li, D., Wang, Z., Sun, P., Jin, Y., Lin, D.H., Hebert, S.C., Giebisch, G., Wang, W.H. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. Erythropoietin and interleukin-3 activate tyrosine phosphorylation of CBL and association with CRK adaptor proteins. Barber, D.L., Mason, J.M., Fukazawa, T., Reedquist, K.A., Druker, B.J., Band, H., D'Andrea, A.D. Blood (1997) [Pubmed]
  8. Amplification, up-regulation and over-expression of C3G (CRK SH3 domain-binding guanine nucleotide-releasing factor) in non-small cell lung cancers. Hirata, T., Nagai, H., Koizumi, K., Okino, K., Harada, A., Onda, M., Nagahata, T., Mikami, I., Hirai, K., Haraguchi, S., Jin, E., Kawanami, O., Shimizu, K., Emi, M. J. Hum. Genet. (2004) [Pubmed]
  9. RIN1 is an ABL tyrosine kinase activator and a regulator of epithelial-cell adhesion and migration. Hu, H., Bliss, J.M., Wang, Y., Colicelli, J. Curr. Biol. (2005) [Pubmed]
  10. CRKL links p210BCR/ABL with paxillin in chronic myelogenous leukemia cells. Salgia, R., Uemura, N., Okuda, K., Li, J.L., Pisick, E., Sattler, M., de Jong, R., Druker, B., Heisterkamp, N., Chen, L.B. J. Biol. Chem. (1995) [Pubmed]
  11. Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins. Matsuda, M., Ota, S., Tanimura, R., Nakamura, H., Matuoka, K., Takenawa, T., Nagashima, K., Kurata, T. J. Biol. Chem. (1996) [Pubmed]
  12. Two species of human CRK cDNA encode proteins with distinct biological activities. Matsuda, M., Tanaka, S., Nagata, S., Kojima, A., Kurata, T., Shibuya, M. Mol. Cell. Biol. (1992) [Pubmed]
  13. DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane. Hasegawa, H., Kiyokawa, E., Tanaka, S., Nagashima, K., Gotoh, N., Shibuya, M., Kurata, T., Matsuda, M. Mol. Cell. Biol. (1996) [Pubmed]
  14. 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. Matsuda, M., Hashimoto, Y., Muroya, K., Hasegawa, H., Kurata, T., Tanaka, S., Nakamura, S., Hattori, S. Mol. Cell. Biol. (1994) [Pubmed]
  15. Differential requirements for ERK1/2 and P38 MAPK activation by thrombin in T cells. Role of P59Fyn and PKCepsilon. Maulon, L., Mari, B., Bertolotto, C., Ricci, J.E., Luciano, F., Belhacene, N., Deckert, M., Baier, G., Auberger, P. Oncogene (2001) [Pubmed]
  16. MEK/ERK-mediated proliferation is negatively regulated by P38 map kinase in the human pancreatic cancer cell line, PANC-1. Ding, X.Z., Adrian, T.E. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  17. Wavelength-specific activation of MAP kinase family proteins by monochromatic UV irradiation. Kabuyama, Y., Homma, M.K., Sekimata, M., Homma, Y. Photochem. Photobiol. (2001) [Pubmed]
  18. Gefitinib and chemotherapy combination studies in five novel human non small cell lung cancer xenografts. Evidence linking EGFR signaling to gefitinib antitumor response. Judde, J.G., Rebucci, M., Vogt, N., de Cremoux, P., Livartowski, A., Chapelier, A., Tran-Perennou, C., Boye, K., Defrance, R., Poupon, M.F., Bras-Gonçalves, R.A. Int. J. Cancer (2007) [Pubmed]
  19. Nitric oxide stimulates COX-2 expression in cultured collecting duct cells through MAP kinases and superoxide but not cGMP. Yang, T., Zhang, A., Pasumarthy, A., Zhang, L., Warnock, Z., Schnermann, J.B. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  20. Regulation of urokinase plasminogen activator by epigallocatechin-3-gallate in human fibrosarcoma cells. Kim, M.H., Jung, M.A., Hwang, Y.S., Jeong, M., Kim, S.M., Ahn, S.J., Shin, B.A., Ahn, B.W., Jung, Y.D. Eur. J. Pharmacol. (2004) [Pubmed]
  21. Mitogen-Activated Protein Kinases Inhibit the ROMK (Kir 1.1)-Like Small Conductance K Channels in the Cortical Collecting Duct. Babilonia, E., Li, D., Wang, Z., Sun, P., Lin, D.H., Jin, Y., Wang, W.H. J. Am. Soc. Nephrol. (2006) [Pubmed]
  22. Paxillin interactions. Turner, C.E. J. Cell. Sci. (2000) [Pubmed]
  23. Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model. Fryknäs, M., Rickardson, L., Wickström, M., Dhar, S., Lövborg, H., Gullbo, J., Nygren, P., Gustafsson, M.G., Isaksson, A., Larsson, R. Journal of biomolecular screening : the official journal of the Society for Biomolecular Screening. (2006) [Pubmed]
  24. Mixed lineage kinase 3 inhibits phorbol myristoyl acetate-induced DNA synthesis but not osteopontin expression in rat mesangial cells. Parameswaran, N., Hall, C.S., Bock, B.C., Sparks, H.V., Gallo, K.A., Spielman, W.S. Mol. Cell. Biochem. (2002) [Pubmed]
  25. Expression of erbB/HER receptors, heregulin and P38 in primary breast cancer using quantitative immunohistochemistry. Esteva, F.J., Hortobagyi, G.N., Sahin, A.A., Smith, T.L., Chin, D.M., Liang, S.Y., Pusztai, L., Buzdar, A.U., Bacus, S.S. Pathol. Oncol. Res. (2001) [Pubmed]
  26. Fine mapping of an apparently targeted latent human herpesvirus type 6 integration site in chromosome band 17p13.3. Morris, C., Luppi, M., McDonald, M., Barozzi, P., Torelli, G. J. Med. Virol. (1999) [Pubmed]
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