| Structural highlights
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] [CBLB_HUMAN] E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome. Negatively regulates TCR (T-cell receptor), BCR (B-cell receptor) and FCER1 (high affinity immunoglobulin epsilon receptor) signal transduction pathways. In naive T-cells, inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 ubiquitination, which impairs its recruitment to the TCR and subsequent activation. In activated T-cells, inhibits PLCG1 activation and calcium mobilization upon restimulation and promotes anergy. In B-cells, acts by ubiquitinating SYK and promoting its proteasomal degradation. May also be involved in EGFR ubiquitination and internalization.[11] [12] [13] [14]
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
The ubiquitin ligases c-Cbl and Cbl-b play a crucial role in receptor downregulation by mediating multiple monoubiquitination of receptors and promoting their sorting for lysosomal degradation. Their function is modulated through interactions with regulatory proteins including CIN85 and PIX, which recognize a proline-arginine motif in Cbl and thus promote or inhibit receptor endocytosis. We report the structures of SH3 domains of CIN85 and beta-PIX in complex with a proline-arginine peptide from Cbl-b. Both structures reveal a heterotrimeric complex containing two SH3 domains held together by a single peptide. Trimerization also occurs in solution and is facilitated by the pseudo-symmetrical peptide sequence. 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. These results provide molecular explanations for a novel mechanism by which Cbl controls receptor downregulation.
Cbl promotes clustering of endocytic adaptor proteins.,Jozic D, Cardenes N, Deribe YL, Moncalian G, Hoeller D, Groemping Y, Dikic I, Rittinger K, Bravo J Nat Struct Mol Biol. 2005 Nov;12(11):972-9. PMID:16228008[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Elly C, Witte S, Zhang Z, Rosnet O, Lipkowitz S, Altman A, Liu YC. Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation. Oncogene. 1999 Feb 4;18(5):1147-56. PMID:10022120 doi:10.1038/sj.onc.1202411
- ↑ Ettenberg SA, Keane MM, Nau MM, Frankel M, Wang LM, Pierce JH, Lipkowitz S. cbl-b inhibits epidermal growth factor receptor signaling. Oncogene. 1999 Mar 11;18(10):1855-66. PMID:10086340 doi:10.1038/sj.onc.1202499
- ↑ Fang D, Wang HY, Fang N, Altman Y, Elly C, Liu YC. Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J Biol Chem. 2001 Feb 16;276(7):4872-8. Epub 2000 Nov 21. PMID:11087752 doi:10.1074/jbc.M008901200
- ↑ Fang D, Liu YC. Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nat Immunol. 2001 Sep;2(9):870-5. PMID:11526404 doi:10.1038/ni0901-870
- ↑ Jozic D, Cardenes N, Deribe YL, Moncalian G, Hoeller D, Groemping Y, Dikic I, Rittinger K, Bravo J. Cbl promotes clustering of endocytic adaptor proteins. Nat Struct Mol Biol. 2005 Nov;12(11):972-9. PMID:16228008 doi:http://dx.doi.org/10.1038/nsmb1000
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