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Gene Review

NEDD9  -  neural precursor cell expressed,...

Homo sapiens

Synonyms: CAS-L, CAS2, CASL, CASS2, CRK-associated substrate-related protein, ...
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Disease relevance of NEDD9

  • Regulation of NEDD9 may be an important means whereby atRA promotes cell spreading and neurite outgrowth in SH-SY5Y human neuroblastoma cells, and NEDD9 represents a new downstream target of atRA and its receptors in the developing hindbrain [1].
  • Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene [2].
  • HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells [3].
  • Three cellular proteins, including species of 300,000 daltons and 107,000 daltons as well as p105-RB, the product of the retinoblastoma susceptibility gene, stably interact with the adenovirus E1A proteins [4].
  • Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention [5].
  • Mechanistic studies suggest diverse cellular roles of HEF1 and highlight its importance in the response to extracellular cues that drive invasion and metastasis [6].

Psychiatry related information on NEDD9

  • The absence of a relation between the periconceptional use of vitamins and neural-tube defects. National Institute of Child Health and Human Development Neural Tube Defects Study Group [7].
  • Three-dimensional computergraphic analysis of apraxia. Neural representations of learned movement [8].
  • Mechanisms that underlie figural emergence support the interpolation of contours and the filling-in of form information [Grossberg, S., & Mingolla, E. Neural dynamics of form perception: Boundary completion, illusory figures and neon colour spreading. Psychological Review, 92, 173-211, 1985] [9].
  • CONCLUSIONS: Neural activity within the medial and lateral orbitofrontal cortex, pregenual ACC, and striatum mediate distinct representations of reward-related information that are deployed at different stages during a decision-making episode [10].
  • Immunoreactivity of the nuclear antigen p105 is associated with plaques and tangles in Alzheimer's disease [11].

High impact information on NEDD9


Chemical compound and disease context of NEDD9


Biological context of NEDD9


Anatomical context of NEDD9


Associations of NEDD9 with chemical compounds

  • NEDD9 expression is also perturbed in vitamin A-deficient embryos [1].
  • Human enhancer of filamentation-1 (HEF1), a multifunctional docking protein, is involved in integrin-based signaling, which affects cell motility, growth, and apoptosis [19].
  • While the generation of the cleaved HEF1 forms is caspase dependent, the accumulation of HEF1 forms is further regulated by the proteasome, as the proteasome inhibitors N-acetyl-L-leucinyl-L-leucinyl-L-norleucinyl and lactacystin enhance their stability [25].
  • Dibutyryl cAMP and forskolin had little or no effect on HEF1 phosphorylation, and the protein kinase A inhibitor H89 failed to detectably inhibit the response to calcitonin, indicating that the G(s)/cAMP/protein kinase A pathway does not mediate the calcitonin effect [26].
  • Phorbol 12-myristate 13-acetate also induced HEF1 tyrosine phosphorylation, and the protein kinase C inhibitor calphostin C completely inhibited both calcitonin- and phorbol 12-myristate 13-acetate-stimulated HEF1 phosphorylation [26].

Physical interactions of NEDD9


Co-localisations of NEDD9

  • MICAL is a cytoplasmic protein and colocalizes with CasL at the perinuclear area [27].
  • The phosphorylated HEF1 colocalized with vinculin and was associated almost exclusively with 0.1% Triton X-100 insoluble material, consistent with its signaling at focal adhesions [3].

Regulatory relationships of NEDD9

  • The molecular mechanisms underlying Smad3-regulated HEF1 degradation are not well understood [31].
  • Focal adhesion kinase regulates beta1 integrin-dependent T cell migration through an HEF1 effector pathway [32].
  • Analysis of a series of beta1 cytoplasmic domain truncations reveals that a truncation of only five amino acids from the carboxyl-terminal end of the beta1 cytoplasmic domain abrogates the ability of the CD2/beta1 chimera to activate tyrosine phosphorylation of HEF1, pp105, or pp115 [33].
  • The HEF1-promoted processes are dependent on the presence of an intact microtubule system and can be inhibited by co-expression of either constitutively active Rac or Cdc42 GTPase [34].

Other interactions of NEDD9

  • TGF-beta1 had no effect on the stability of either HEF1 protein or mRNA [19].
  • Here we report our studies that demonstrate the function of AIP4 as an ubiquitin E3 ligase for HEF1 [20].
  • Exposure of rat embryos to excess atRA at times ranging from E9.25 to E12 leads to altered NEDD9 expression in the developing hindbrain within 6 hr [1].
  • Together, our results indicate that beta1 integrin-stimulated T cell migration requires a linear beta1 integrin-FAK-HEF1 effector pathway [32].
  • MICAL associates with CasL through this PPKPP sequence [27].

Analytical, diagnostic and therapeutic context of NEDD9


  1. Crk-associated substrate (Cas) family member, NEDD9, is regulated in human neuroblastoma cells and in the embryonic hindbrain by all-trans retinoic acid. Merrill, R.A., See, A.W., Wertheim, M.L., Clagett-Dame, M. Dev. Dyn. (2004) [Pubmed]
  2. Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Kim, M., Gans, J.D., Nogueira, C., Wang, A., Paik, J.H., Feng, B., Brennan, C., Hahn, W.C., Cordon-Cardo, C., Wagner, S.N., Flotte, T.J., Duncan, L.M., Granter, S.R., Chin, L. Cell (2006) [Pubmed]
  3. HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells. Natarajan, M., Stewart, J.E., Golemis, E.A., Pugacheva, E.N., Alexandropoulos, K., Cox, B.D., Wang, W., Grammer, J.R., Gladson, C.L. Oncogene (2006) [Pubmed]
  4. Cellular targets for transformation by the adenovirus E1A proteins. Whyte, P., Williamson, N.M., Harlow, E. Cell (1989) [Pubmed]
  5. Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. Berry, R.J., Li, Z., Erickson, J.D., Li, S., Moore, C.A., Wang, H., Mulinare, J., Zhao, P., Wong, L.Y., Gindler, J., Hong, S.X., Correa, A. N. Engl. J. Med. (1999) [Pubmed]
  6. A new central scaffold for metastasis: parsing HEF1/Cas-L/NEDD9. O'Neill, G.M., Seo, S., Serebriiskii, I.G., Lessin, S.R., Golemis, E.A. Cancer Res. (2007) [Pubmed]
  7. The absence of a relation between the periconceptional use of vitamins and neural-tube defects. National Institute of Child Health and Human Development Neural Tube Defects Study Group. Mills, J.L., Rhoads, G.G., Simpson, J.L., Cunningham, G.C., Conley, M.R., Lassman, M.R., Walden, M.E., Depp, O.R., Hoffman, H.J. N. Engl. J. Med. (1989) [Pubmed]
  8. Three-dimensional computergraphic analysis of apraxia. Neural representations of learned movement. Poizner, H., Mack, L., Verfaellie, M., Rothi, L.J., Heilman, K.M. Brain (1990) [Pubmed]
  9. Electrophysiological correlates of similarity-based interference during detection of visual forms. Conci, M., Gramann, K., Müller, H.J., Elliott, M.A. Journal of cognitive neuroscience. (2006) [Pubmed]
  10. Distinct portions of anterior cingulate cortex and medial prefrontal cortex are activated by reward processing in separable phases of decision-making cognition. Rogers, R.D., Ramnani, N., Mackay, C., Wilson, J.L., Jezzard, P., Carter, C.S., Smith, S.M. Biol. Psychiatry (2004) [Pubmed]
  11. Immunoreactivity of the nuclear antigen p105 is associated with plaques and tangles in Alzheimer's disease. Masliah, E., Mallory, M., Alford, M., Hansen, L.A., Saitoh, T. Lab. Invest. (1993) [Pubmed]
  12. The cellular 107K protein that binds to adenovirus E1A also associates with the large T antigens of SV40 and JC virus. Dyson, N., Buchkovich, K., Whyte, P., Harlow, E. Cell (1989) [Pubmed]
  13. The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Buchkovich, K., Duffy, L.A., Harlow, E. Cell (1989) [Pubmed]
  14. Cloning of an NF-kappa B subunit which stimulates HIV transcription in synergy with p65. Schmid, R.M., Perkins, N.D., Duckett, C.S., Andrews, P.C., Nabel, G.J. Nature (1991) [Pubmed]
  15. Letter: Neural crest, limb development, and thalidomide embryopathy. Gardner, E., O'Rahilly, R. Lancet (1976) [Pubmed]
  16. Detection by monoclonal antibodies of an early membrane protein induced by Epstein-Barr virus. Balachandran, N., Pittari, J., Hutt-Fletcher, L.M. J. Virol. (1986) [Pubmed]
  17. A neural network classifier for cerebral perfusion imaging. Chan, K.H., Johnson, K.A., Becker, J.A., Satlin, A., Mendelson, J., Garada, B., Holman, B.L. J. Nucl. Med. (1994) [Pubmed]
  18. 17 beta-estradiol inhibits tumor necrosis factor-alpha-induced nuclear factor-kappa B activation by increasing nuclear factor-kappa B p105 level in MCF-7 breast cancer cells. Hsu, S.M., Chen, Y.C., Jiang, M.C. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  19. Regulation of HEF1 expression and phosphorylation by TGF-beta 1 and cell adhesion. Zheng, M., McKeown-Longo, P.J. J. Biol. Chem. (2002) [Pubmed]
  20. Atrophin-1-interacting protein 4/human Itch is a ubiquitin E3 ligase for human enhancer of filamentation 1 in transforming growth factor-beta signaling pathways. Feng, L., Guedes, S., Wang, T. J. Biol. Chem. (2004) [Pubmed]
  21. Of mice and men: cancer gene discovery using comparative oncogenomics. Tomlins, S.A., Chinnaiyan, A.M. Cancer Cell (2006) [Pubmed]
  22. T cell receptor-mediated tyrosine phosphorylation of Cas-L, a 105-kDa Crk-associated substrate-related protein, and its association of Crk and C3G. Ohashi, Y., Tachibana, K., Kamiguchi, K., Fujita, H., Morimoto, C. J. Biol. Chem. (1998) [Pubmed]
  23. Human enhancer of filamentation 1, a novel p130cas-like docking protein, associates with focal adhesion kinase and induces pseudohyphal growth in Saccharomyces cerevisiae. Law, S.F., Estojak, J., Wang, B., Mysliwiec, T., Kruh, G., Golemis, E.A. Mol. Cell. Biol. (1996) [Pubmed]
  24. Involvement of p130(Cas) and p105(HEF1), a novel Cas-like docking protein, in a cytoskeleton-dependent signaling pathway initiated by ligation of integrin or antigen receptor on human B cells. Manié, S.N., Beck, A.R., Astier, A., Law, S.F., Canty, T., Hirai, H., Druker, B.J., Avraham, H., Haghayeghi, N., Sattler, M., Salgia, R., Griffin, J.D., Golemis, E.A., Freedman, A.S. J. Biol. Chem. (1997) [Pubmed]
  25. The docking protein HEF1 is an apoptotic mediator at focal adhesion sites. Law, S.F., O'Neill, G.M., Fashena, S.J., Einarson, M.B., Golemis, E.A. Mol. Cell. Biol. (2000) [Pubmed]
  26. Cytoskeleton-dependent tyrosine phosphorylation of the p130(Cas) family member HEF1 downstream of the G protein-coupled calcitonin receptor. Calcitonin induces the association of HEF1, paxillin, and focal adhesion kinase. Zhang, Z., Hernandez-Lagunas, L., Horne, W.C., Baron, R. J. Biol. Chem. (1999) [Pubmed]
  27. MICAL, a novel CasL interacting molecule, associates with vimentin. Suzuki, T., Nakamoto, T., Ogawa, S., Seo, S., Matsumura, T., Tachibana, K., Morimoto, C., Hirai, H. J. Biol. Chem. (2002) [Pubmed]
  28. A novel ability of Smad3 to regulate proteasomal degradation of a Cas family member HEF1. Liu, X., Elia, A.E., Law, S.F., Golemis, E.A., Farley, J., Wang, T. EMBO J. (2000) [Pubmed]
  29. Members of the Zyxin family of LIM proteins interact with members of the p130Cas family of signal transducers. Yi, J., Kloeker, S., Jensen, C.C., Bockholt, S., Honda, H., Hirai, H., Beckerle, M.C. J. Biol. Chem. (2002) [Pubmed]
  30. G protein-coupled receptors in gastrointestinal physiology. IV. Neural regulation of gastrointestinal smooth muscle. Sanders, K.M. Am. J. Physiol. (1998) [Pubmed]
  31. Direct interaction between Smad3, APC10, CDH1 and HEF1 in proteasomal degradation of HEF1. Nourry, C., Maksumova, L., Pang, M., Liu, X., Wang, T. BMC Cell Biol. (2004) [Pubmed]
  32. Focal adhesion kinase regulates beta1 integrin-dependent T cell migration through an HEF1 effector pathway. van Seventer, G.A., Salmen, H.J., Law, S.F., O'Neill, G.M., Mullen, M.M., Franz, A.M., Kanner, S.B., Golemis, E.A., van Seventer, J.M. Eur. J. Immunol. (2001) [Pubmed]
  33. Structural requirements for beta1 integrin-mediated tyrosine phosphorylation in human T cells. Finkelstein, L.D., Reynolds, P.J., Hunt, S.W., Shimizu, Y. J. Immunol. (1997) [Pubmed]
  34. The Cas family docking protein, HEF1, promotes the formation of neurite-like membrane extensions. Bargon, S.D., Gunning, P.W., O'Neill, G.M. Biochim. Biophys. Acta (2005) [Pubmed]
  35. Ligation of the T cell antigen receptor induces tyrosine phosphorylation of p105CasL, a member of the p130Cas-related docking protein family, and its subsequent binding to the Src homology 2 domain of c-Crk. Kanda, H., Mimura, T., Morino, N., Hamasaki, K., Nakamoto, T., Hirai, H., Morimoto, C., Yazaki, Y., Nojima, Y. Eur. J. Immunol. (1997) [Pubmed]
  36. Identification of an atypical lipoprotein-binding protein from human aortic smooth muscle as T-cadherin. Tkachuk, V.A., Bochkov, V.N., Philippova, M.P., Stambolsky, D.V., Kuzmenko, E.S., Sidorova, M.V., Molokoedov, A.S., Spirov, V.G., Resink, T.J. FEBS Lett. (1998) [Pubmed]
  37. Oxidative stress oppositely modulates protein tyrosine phosphorylation stimulated by muscarinic G protein-coupled and epidermal growth factor receptors. Jope, R.S., Song, L., Grimes, C.A., Zhang, L. J. Neurosci. Res. (1999) [Pubmed]
  38. The hematopoietic isoform of cas-hef1-associated signal transducer regulates chemokine-induced inside-out signaling and T cell trafficking. Regelmann, A.G., Danzl, N.M., Wanjalla, C., Alexandropoulos, K. Immunity (2006) [Pubmed]
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