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Gene Review

SH3KBP1  -  SH3-domain kinase binding protein 1

Homo sapiens

Synonyms: CD2-binding protein 3, CD2BP3, CIN85, Cbl-interacting protein of 85 kDa, GIG10, ...
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Disease relevance of SH3KBP1

  • Herpes simplex virus 1 infected cell protein 0 forms a complex with CIN85 and Cbl and mediates the degradation of EGF receptor from cell surfaces [1].
  • Collectively, our data indicate that CIN85 might play an important role in HSV-1 infection [2].

High impact information on SH3KBP1

  • Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors [3].
  • CIN85 was constitutively associated with endophilins, whereas CIN85 binding to the distal carboxy terminus of Cbl was increased on EGF stimulation [3].
  • Cbl, in turn, binds and ubiquitinates activated HGF receptor, and by recruiting the endophilin-CIN85 complex, it regulates receptor internalization [4].
  • Furthermore, by means of their Src-homology 3 domains, endophilins are able to bind CIN85, a recently identified protein that interacts with the Cbl proto-oncogene [4].
  • CIN85 and Cbl are involved in endocytosis and negative regulation of numerous receptor tyrosine kinases [1].

Biological context of SH3KBP1


Anatomical context of SH3KBP1

  • These results indicate a potential role of CIN85 in the B cell receptor-mediated signaling pathway [8].
  • Cbl rapidly recruits CIN85 (Cbl-interacting protein of 85K; ref. 6) and endophilins (regulatory components of clathrin-coated vesicles) to form a complex with activated EGF receptors, thus controlling receptor internalization [3].
  • Cbl-b and monoubiquitinated CIN85 are found in the complex with polyubiquitinated EGF receptors during prolonged EGF stimulation and are degraded together in the lysosome [9].
  • CIN85 mRNA is expressed ubiquitously in normal human tissues and cancer cell lines analyzed [10].
  • Here, we demonstrate that plaque formation by HSV-1 is reduced on HeLa cells expressing CIN85 ectopically [2].

Associations of SH3KBP1 with chemical compounds

  • Thus, our data demonstrate that Cbl/Cbl-b can mediate polyubiquitination of cargo as well as monoubiquitination of CIN85 to control endosomal sorting and degradation of receptor tyrosine kinases [9].
  • This motif was indispensable for CIN85 binding to Cbl/Cbl-b, to other CIN85 SH3 domains' effectors, and for mediating an intramolecular interaction between the SH3-A domain and the proline-rich region of CIN85 [11].
  • 2. Two of these DESTs, GIG10 and GIG18, are rapidly induced by dexamethasone within 2 h of treatment [12].
  • We found that CIN85 overexpression inhibits the FcepsilonRI-induced tyrosine phosphorylation of phospholipase Cgamma, thus altering calcium mobilization [13].

Physical interactions of SH3KBP1

  • Coimmunoprecipitation experiments using mammalian cells revealed that CIN85 directly bound to BLNK through its SH3 domains [8].
  • Interaction trap cloning was used to identify a CD2 cytoplasmic tail-binding protein termed CD2BP3 [14].
  • Further characterization of CIN85 binding to ASAP1 revealed that formation of the complex is independent on cell stimulation [15].

Regulatory relationships of SH3KBP1

  • Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors [9].
  • Moreover, ternary complexes of CIN85 and Cbl are formed in vivo and are important for the ability of Cbl to promote epidermal growth factor receptor (EGFR) downregulation [16].

Other interactions of SH3KBP1


Analytical, diagnostic and therapeutic context of SH3KBP1


  1. Herpes simplex virus 1 infected cell protein 0 forms a complex with CIN85 and Cbl and mediates the degradation of EGF receptor from cell surfaces. Liang, Y., Kurakin, A., Roizman, B. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Overexpression of CIN85 suppresses the growth of herpes simplex virus in HeLa cells. Narita, T., Ando, A., Mikami, Y., Taniyama, T. Exp. Cell Res. (2005) [Pubmed]
  3. Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Soubeyran, P., Kowanetz, K., Szymkiewicz, I., Langdon, W.Y., Dikic, I. Nature (2002) [Pubmed]
  4. The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Petrelli, A., Gilestro, G.F., Lanzardo, S., Comoglio, P.M., Migone, N., Giordano, S. Nature (2002) [Pubmed]
  5. Assignment of SH3KBP1 to human chromosome band Xp22.1-->p21.3 by in situ hybridization. Narita, T., Amano, F., Yoshizaki, K., Nishimoto, N., Nishimura, T., Tajima, T., Namiki, H., Taniyama, T. Cytogenet. Cell Genet. (2001) [Pubmed]
  6. CIN85 associates with TNF receptor 1 via Src and modulates TNF-alpha-induced apoptosis. Narita, T., Nishimura, T., Yoshizaki, K., Taniyama, T. Exp. Cell Res. (2005) [Pubmed]
  7. Phosphorylation of the proline-rich domain of Xp95 modulates Xp95 interaction with partner proteins. Dejournett, R.E., Kobayashi, R., Pan, S., Wu, C., Etkin, L.D., Clark, R.B., B??gler, O., Kuang, J. Biochem. J. (2007) [Pubmed]
  8. Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes. Watanabe, S., Take, H., Takeda, K., Yu, Z.X., Iwata, N., Kajigaya, S. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  9. Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors. Haglund, K., Shimokawa, N., Szymkiewicz, I., Dikic, I. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  10. Cloning and characterization of a novel adaptor protein, CIN85, that interacts with c-Cbl. Take, H., Watanabe, S., Takeda, K., Yu, Z.X., Iwata, N., Kajigaya, S. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  11. Identification of a novel proline-arginine motif involved in CIN85-dependent clustering of Cbl and down-regulation of epidermal growth factor receptors. Kowanetz, K., Szymkiewicz, I., Haglund, K., Kowanetz, M., Husnjak, K., Taylor, J.D., Soubeyran, P., Engstrom, U., Ladbury, J.E., Dikic, I. J. Biol. Chem. (2003) [Pubmed]
  12. Isolation of differentially expressed sequence tags from steroid-responsive cells using mRNA differential display. Chapman, M.S., Qu, N., Pascoe, S., Chen, W.X., Apostol, C., Gordon, D., Miesfeld, R.L. Mol. Cell. Endocrinol. (1995) [Pubmed]
  13. The adaptor molecule CIN85 regulates Syk tyrosine kinase level by activating the ubiquitin-proteasome degradation pathway. Peruzzi, G., Molfetta, R., Gasparrini, F., Vian, L., Morrone, S., Piccoli, M., Frati, L., Santoni, A., Paolini, R. J. Immunol. (2007) [Pubmed]
  14. CD2BP3, CIN85 and the structurally related adaptor protein CMS bind to the same CD2 cytoplasmic segment, but elicit divergent functional activities. Tibaldi, E.V., Reinherz, E.L. Int. Immunol. (2003) [Pubmed]
  15. CIN85 associates with multiple effectors controlling intracellular trafficking of epidermal growth factor receptors. Kowanetz, K., Husnjak, K., Höller, D., Kowanetz, M., Soubeyran, P., Hirsch, D., Schmidt, M.H., Pavelic, K., De Camilli, P., Randazzo, P.A., Dikic, I. Mol. Biol. Cell (2004) [Pubmed]
  16. Cbl promotes clustering of endocytic adaptor proteins. Jozic, D., Cárdenes, N., Deribe, Y.L., Moncalián, G., Hoeller, D., Groemping, Y., Dikic, I., Rittinger, K., Bravo, J. Nature structural & molecular biology. (2005) [Pubmed]
  17. Linking the T cell surface protein CD2 to the actin-capping protein CAPZ via CMS and CIN85. Hutchings, N.J., Clarkson, N., Chalkley, R., Barclay, A.N., Brown, M.H. J. Biol. Chem. (2003) [Pubmed]
  18. Atypical recognition consensus of CIN85/SETA/Ruk SH3 domains revealed by target-assisted iterative screening. Kurakin, A.V., Wu, S., Bredesen, D.E. J. Biol. Chem. (2003) [Pubmed]
  19. CIN85 is localized at synapses and forms a complex with S-SCAM via dendrin. Kawata, A., Iida, J., Ikeda, M., Sato, Y., Mori, H., Kansaku, A., Sumita, K., Fujiwara, N., Rokukawa, C., Hamano, M., Hirabayashi, S., Hata, Y. J. Biochem. (2006) [Pubmed]
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