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Gene Review

Nck1  -  non-catalytic region of tyrosine kinase...

Mus musculus

Synonyms: 6330586M15Rik, Cytoplasmic protein NCK1, D230010O13Rik, NCK adaptor protein 1, Nck, ...
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Disease relevance of Nck1


High impact information on Nck1

  • Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation [4].
  • Finally, by interfering with Nck-CD3 epsilon association in vivo, we demonstrate that TCR-CD3 recruitment of Nck is critical for maturation of the immune synapse and for T cell activation [4].
  • Tyrosine phosphorylation of A36R results in a direct interaction with the adaptor protein Nck and the recruitment of the Ena/VASP family member N-WASP to the site of actin assembly [5].
  • IRS-1 also has binding sites for Syp and Nck and other src homology 2 (SH2) signalling molecules [6].
  • There is a nearby site specific for binding another adapter, Nck, and these sites also bind Grb-2 [7].

Biological context of Nck1


Anatomical context of Nck1

  • Mammalian Nck1 and Nck2 are closely related adaptor proteins that possess three SH3 domains, followed by an SH2 domain, and are implicated in coupling phosphotyrosine signals to polypeptides that regulate the actin cytoskeleton [8].
  • Dok-related protein negatively regulates T cell development via its RasGTPase-activating protein and Nck docking sites [10].
  • Cell fractionation studies demonstrated that the presence of Nck in purified ribosomal fractions was enhanced after insulin stimulation, suggesting that growth factors dynamically regulate translocation of Nck to ribosomes [12].
  • An unmyristoylated Nck SH3 domain construct, which localizes to the cytosol and nucleus, also activated Abl but only at high levels of expression [13].
  • A myristoylated Nck SH3 domain construct, which is expected to localize to membranes, potently activated Abl when expressed at low levels [13].

Associations of Nck1 with chemical compounds


Physical interactions of Nck1

  • Importantly, functional RasGAP and Nck binding sites were found to be essential for the biological effects of DokR in vitro and in vivo [10].
  • Pull-down experiments demonstrated the inability of Nck to bind to the CD3epsilon PRS in thymocytes from mutant mice after TCR ligation [14].
  • Analysis of tyrosine-phosphorylated proteins demonstrated that Crk-associated substrate (p130(Cas)), not the activated PDGFbetaR itself, is the major Nck SH2 domain-binding protein in PDGF-B-stimulated cells [18].
  • Moreover, tyrosine-phosphorylated Ack forms a stable complex with the adapter protein Nck via its SH2 domain [19].

Enzymatic interactions of Nck1


Co-localisations of Nck1


Regulatory relationships of Nck1

  • We find that a construct encoding the first two Src homology 3 (SH3) domains of the Src homology 2/SH3 adaptor protein Nck can activate c-Abl in human 293T cells [13].
  • We report here that Nck adaptors are required for cytoskeletal reorganization and chemotaxis stimulated by PDGF-B [18].
  • We investigated the role of mammalian Nck adaptors in signaling from the activated platelet-derived growth factor (PDGF) receptor (PDGFbetaR) to the actin cytoskeleton [18].
  • Furthermore, expression of dominant-negative forms of Nck inhibited BCR-induced JNK activation [20].
  • Requirement of Nck adaptors for actin dynamics and cell migration stimulated by platelet-derived growth factor B [18].
  • Src- and Tks5-driven matrix proteolysis and actin assembly in invadopodia are enhanced by Nck1 or Nck2 overexpression and inhibited by Nck1 depletion [21].

Other interactions of Nck1

  • Finally, mutation of the Nck-binding site of EphB1 (Y594F) interrupts the interaction between Nck, paxillin, and EphB1 [22].
  • Dok-4 and dok-5 do not associate with rasGAP or Nck, in contrast to p62dok and dok-2 [23].
  • Three SH2 domain-containing proteins, c-Src, Nck, and Ras-GAP, were found to associate with Cav-2 in a phosphorylation-dependent manner [24].
  • Crk, a cellular homolog of v-crk, is an SH2 and SH3 domain-containing adaptor protein related to Grb2 and Nck, two proteins which have been shown to be involved in growth factor signal transduction [25].
  • In contrast, the protein levels of GRB2, Nck, Syp, and GLUT-1 were dramatically elevated in KKAy fat, with less striking changes in liver [26].

Analytical, diagnostic and therapeutic context of Nck1


  1. Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Jones, N., Blasutig, I.M., Eremina, V., Ruston, J.M., Bladt, F., Li, H., Huang, H., Larose, L., Li, S.S., Takano, T., Quaggin, S.E., Pawson, T. Nature (2006) [Pubmed]
  2. Cloning, sequencing, and overexpression of SH2/SH3 adaptor protein Nck from mouse thymus. Park, D. Mol. Cells (1997) [Pubmed]
  3. Two species of mRNAs for the fyn proto-oncogene are produced by an alternative polyadenylation. Lee, C., Kim, M.G., Jeon, S.H., Park, D.E., Park, S.D., Seong, R.H. Mol. Cells (1998) [Pubmed]
  4. Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Gil, D., Schamel, W.W., Montoya, M., Sánchez-Madrid, F., Alarcón, B. Cell (2002) [Pubmed]
  5. Actin-based motility of vaccinia virus mimics receptor tyrosine kinase signalling. Frischknecht, F., Moreau, V., Röttger, S., Gonfloni, S., Reckmann, I., Superti-Furga, G., Way, M. Nature (1999) [Pubmed]
  6. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Tamemoto, H., Kadowaki, T., Tobe, K., Yagi, T., Sakura, H., Hayakawa, T., Terauchi, Y., Ueki, K., Kaburagi, Y., Satoh, S. Nature (1994) [Pubmed]
  7. Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites. Ren, R., Ye, Z.S., Baltimore, D. Genes Dev. (1994) [Pubmed]
  8. The murine Nck SH2/SH3 adaptors are important for the development of mesoderm-derived embryonic structures and for regulating the cellular actin network. Bladt, F., Aippersbach, E., Gelkop, S., Strasser, G.A., Nash, P., Tafuri, A., Gertler, F.B., Pawson, T. Mol. Cell. Biol. (2003) [Pubmed]
  9. The adaptor protein Nck1 mediates endothelin A receptor-regulated cell migration through the Cdc42-dependent c-Jun N-terminal kinase pathway. Miyamoto, Y., Yamauchi, J., Mizuno, N., Itoh, H. J. Biol. Chem. (2004) [Pubmed]
  10. Dok-related protein negatively regulates T cell development via its RasGTPase-activating protein and Nck docking sites. Gugasyan, R., Quilici, C., I, S.T., Grail, D., Verhagen, A.M., Roberts, A., Kitamura, T., Dunn, A.R., Lock, P. J. Cell Biol. (2002) [Pubmed]
  11. c-Abl phosphorylates Dok1 to promote filopodia during cell spreading. Woodring, P.J., Meisenhelder, J., Johnson, S.A., Zhou, G.L., Field, J., Shah, K., Bladt, F., Pawson, T., Niki, M., Pandolfi, P.P., Wang, J.Y., Hunter, T. J. Cell Biol. (2004) [Pubmed]
  12. Modulation of protein translation by Nck-1. Kebache, S., Zuo, D., Chevet, E., Larose, L. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  13. Activation of the Abl tyrosine kinase in vivo by Src homology 3 domains from the Src homology 2/Src homology 3 adaptor Nck. Smith, J.M., Katz, S., Mayer, B.J. J. Biol. Chem. (1999) [Pubmed]
  14. The CD3epsilon proline-rich sequence, and its interaction with Nck, is not required for T cell development and function. Szymczak, A.L., Workman, C.J., Gil, D., Dilioglou, S., Vignali, K.M., Palmer, E., Vignali, D.A. J. Immunol. (2005) [Pubmed]
  15. Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells. Holland, S.J., Gale, N.W., Gish, G.D., Roth, R.A., Songyang, Z., Cantley, L.C., Henkemeyer, M., Yancopoulos, G.D., Pawson, T. EMBO J. (1997) [Pubmed]
  16. Independent SH2-binding sites mediate interaction of Dok-related protein with RasGTPase-activating protein and Nck. Lock, P., Casagranda, F., Dunn, A.R. J. Biol. Chem. (1999) [Pubmed]
  17. The SH2/SH3 domain-containing protein Nck is recognized by certain anti-phospholipase C-gamma 1 monoclonal antibodies, and its phosphorylation on tyrosine is stimulated by platelet-derived growth factor and epidermal growth factor treatment. Meisenhelder, J., Hunter, T. Mol. Cell. Biol. (1992) [Pubmed]
  18. Requirement of Nck adaptors for actin dynamics and cell migration stimulated by platelet-derived growth factor B. Rivera, G.M., Antoku, S., Gelkop, S., Shin, N.Y., Hanks, S.K., Pawson, T., Mayer, B.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  19. Activation of the nonreceptor protein tyrosine kinase Ack by multiple extracellular stimuli. Galisteo, M.L., Yang, Y., Ureña, J., Schlessinger, J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  20. Src homology region 2 domain-containing phosphatase 1 positively regulates B cell receptor-induced apoptosis by modulating association of B cell linker protein with Nck and activation of c-Jun NH2-terminal kinase. Mizuno, K., Tagawa, Y., Mitomo, K., Watanabe, N., Katagiri, T., Ogimoto, M., Yakura, H. J. Immunol. (2002) [Pubmed]
  21. Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation. Stylli, S.S., Stacey, T.T., Verhagen, A.M., Xu, S.S., Pass, I., Courtneidge, S.A., Lock, P. J. Cell. Sci. (2009) [Pubmed]
  22. EphB1-mediated cell migration requires the phosphorylation of paxillin at Tyr-31/Tyr-118. Vindis, C., Teli, T., Cerretti, D.P., Turner, C.E., Huynh-Do, U. J. Biol. Chem. (2004) [Pubmed]
  23. Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation. Grimm, J., Sachs, M., Britsch, S., Di Cesare, S., Schwarz-Romond, T., Alitalo, K., Birchmeier, W. J. Cell Biol. (2001) [Pubmed]
  24. Tyrosine phosphorylation of caveolin-2 at residue 27: differences in the spatial and temporal behavior of phospho-Cav-2 (pY19 and pY27). Wang, X.B., Lee, H., Capozza, F., Marmon, S., Sotgia, F., Brooks, J.W., Campos-Gonzalez, R., Lisanti, M.P. Biochemistry (2004) [Pubmed]
  25. Insulin-like growth factor-I stimulates tyrosine phosphorylation of endogenous c-Crk. Beitner-Johnson, D., LeRoith, D. J. Biol. Chem. (1995) [Pubmed]
  26. Compensatory alterations for insulin signal transduction and glucose transport in insulin-resistant diabetes. Bonini, J.A., Colca, J.R., Dailey, C., White, M., Hofmann, C. Am. J. Physiol. (1995) [Pubmed]
  27. The Nck SH2/SH3 adaptor protein is present in the nucleus and associates with the nuclear protein SAM68. Lawe, D.C., Hahn, C., Wong, A.J. Oncogene (1997) [Pubmed]
  28. R-Ras contains a proline-rich site that binds to SH3 domains and is required for integrin activation by R-Ras. Wang, B., Zou, J.X., Ek-Rylander, B., Ruoslahti, E. J. Biol. Chem. (2000) [Pubmed]
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