| Structural highlights
2k6d is a 2 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Gene: | SH3KBP1, CIN85 (HUMAN), RPS27A, UBA80, UBCEP1, UBA52, UBCEP2, UBB, UBC (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum |
Function
[SH3K1_HUMAN] Adapter protein involved in regulating diverse signal transduction pathways. Involved in the regulation of endocytosis and lysosomal degradation of ligand-induced receptor tyrosine kinases, including EGFR and MET/hepatocyte growth factor receptor, through a association with CBL and endophilins. The association with CBL, and thus the receptor internalization, may inhibited by an interaction with PDCD6IP and/or SPRY2. Involved in regulation of ligand-dependent endocytosis of the IgE receptor. Attenuates phosphatidylinositol 3-kinase activity by interaction with its regulatory subunit (By similarity). May be involved in regulation of cell adhesion; promotes the interaction between TTK2B and PDCD6IP. May be involved in the regulation of cellular stress response via the MAPK pathways through its interaction with MAP3K4. Is involved in modulation of tumor necrosis factor mediated apoptosis. Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape and migration.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
CIN85 is an adaptor protein linking the ubiquitin ligase Cbl and clathrin-binding proteins in clathrin-mediated receptor endocytosis. The SH3 domains of CIN85 bind to a proline-rich region of Cbl. Here we show that all three SH3 domains of CIN85 bind to ubiquitin. We also present a data-based structural model of the CIN85 SH3-C domain in complex with ubiquitin. In this complex, ubiquitin binds to the canonical interaction surface of the SH3 domain for proline-rich ligands and mimics the PPII helix, and we provide evidence that ubiquitin competes with these ligands for binding. We demonstrate that disruption of ubiquitin binding results in constitutive ubiquitination of CIN85 and an increased level of ubiquitination of EGFR in the absence of EGF stimulation. These results suggest that competition between Cbl and ubiquitin binding to CIN85 regulates Cbl function and EGFR endocytosis.
Interactions between the Three CIN85 SH3 Domains and Ubiquitin: Implications for CIN85 Ubiquitination.,Bezsonova I, Bruce MC, Wiesner S, Lin H, Rotin D, Forman-Kay JD Biochemistry. 2008 Aug 5. PMID:18680311[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Szymkiewicz I, Kowanetz K, Soubeyran P, Dinarina A, Lipkowitz S, Dikic I. CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases. J Biol Chem. 2002 Oct 18;277(42):39666-72. Epub 2002 Aug 12. PMID:12177062 doi:10.1074/jbc.M205535200
- ↑ Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I. Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature. 2002 Mar 14;416(6877):183-7. PMID:11894095 doi:10.1038/416183a
- ↑ Petrelli A, Gilestro GF, Lanzardo S, Comoglio PM, Migone N, Giordano S. The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Nature. 2002 Mar 14;416(6877):187-90. PMID:11894096 doi:10.1038/416187a
- ↑ Schmidt MH, Chen B, Randazzo LM, Bogler O. SETA/CIN85/Ruk and its binding partner AIP1 associate with diverse cytoskeletal elements, including FAKs, and modulate cell adhesion. J Cell Sci. 2003 Jul 15;116(Pt 14):2845-55. Epub 2003 May 27. PMID:12771190 doi:10.1242/jcs.00522
- ↑ Schmidt MH, Furnari FB, Cavenee WK, Bogler O. Epidermal growth factor receptor signaling intensity determines intracellular protein interactions, ubiquitination, and internalization. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6505-10. Epub 2003 May 6. PMID:12734385 doi:10.1073/pnas.1031790100
- ↑ Kowanetz K, Husnjak K, Holler D, Kowanetz M, Soubeyran P, Hirsch D, Schmidt MH, Pavelic K, De Camilli P, Randazzo PA, Dikic I. CIN85 associates with multiple effectors controlling intracellular trafficking of epidermal growth factor receptors. Mol Biol Cell. 2004 Jul;15(7):3155-66. Epub 2004 Apr 16. PMID:15090612 doi:10.1091/mbc.E03-09-0683
- ↑ Aissouni Y, Zapart G, Iovanna JL, Dikic I, Soubeyran P. CIN85 regulates the ability of MEKK4 to activate the p38 MAP kinase pathway. Biochem Biophys Res Commun. 2005 Dec 16;338(2):808-14. Epub 2005 Oct 18. PMID:16256071 doi:10.1016/j.bbrc.2005.10.032
- ↑ Narita T, Nishimura T, Yoshizaki K, Taniyama T. CIN85 associates with TNF receptor 1 via Src and modulates TNF-alpha-induced apoptosis. Exp Cell Res. 2005 Mar 10;304(1):256-64. Epub 2004 Dec 1. PMID:15707590 doi:S0014-4827(04)00682-2
- ↑ Molfetta R, Belleudi F, Peruzzi G, Morrone S, Leone L, Dikic I, Piccoli M, Frati L, Torrisi MR, Santoni A, Paolini R. CIN85 regulates the ligand-dependent endocytosis of the IgE receptor: a new molecular mechanism to dampen mast cell function. J Immunol. 2005 Oct 1;175(7):4208-16. PMID:16177060
- ↑ Bai SW, Herrera-Abreu MT, Rohn JL, Racine V, Tajadura V, Suryavanshi N, Bechtel S, Wiemann S, Baum B, Ridley AJ. Identification and characterization of a set of conserved and new regulators of cytoskeletal organization, cell morphology and migration. BMC Biol. 2011 Aug 11;9:54. doi: 10.1186/1741-7007-9-54. PMID:21834987 doi:10.1186/1741-7007-9-54
- ↑ Bezsonova I, Bruce MC, Wiesner S, Lin H, Rotin D, Forman-Kay JD. Interactions between the Three CIN85 SH3 Domains and Ubiquitin: Implications for CIN85 Ubiquitination. Biochemistry. 2008 Aug 5. PMID:18680311 doi:10.1021/bi800439t
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