P22681

FUNCTION: Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, EGFR, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The Tyr-731 phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. PATHWAY: Protein modification; protein ubiquitination. SUBUNIT: Interacts (phosphorylated at Tyr-731) with PIK3R1. Associates with NCK via its SH3 domain. The phosphorylated C- terminus interacts with CD2AP via its second SH3 domain. Binds to UBE2L3. Interacts with adapters SLA, SLA2 and with the phosphorylated C-terminus of SH2B2. Interacts with EGFR, SYK and ZAP70 via the highly conserved Cbl-N region. Also interacts with SORBS1 and INPPL1/SHIP2. Interacts with phosphorylated LAT2. May interact with CBLB (By similarity). Interacts with ALK, AXL, BLK, FGR and FGFR2. Interacts with CSF1R, EPHB1, FLT1, KDR, PDGFRA and PDGFRB; regulates receptor degradation through ubiquitination. Interacts with HCK and LYN. Interacts with TEK/TIE2 (tyrosine phosphorylated). SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Note=Colocalizes with FGFR2 in lipid rafts at the cell membrane. DOMAIN: The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme. DOMAIN: The N-terminus is composed of the phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain. PTM: Phosphorylated on tyrosine residues by ALK, EGFR, SYK, FYN and ZAP70 (By similarity). Phosphorylated on tyrosine residues in response to FLT1 and KIT signaling. Phosphorylated on tyrosine residues by INSR and FGR. Phosphorylated on several tyrosine residues by constitutively activated FGFR3. Not phosphorylated at Tyr-731 by FGFR3. Phosphorylated on tyrosine residues by activated CSF1R, PDGFRA and PDGFRB. Phosphorylated on tyrosine residues by HCK. PTM: Ubiquitinated, leading to its degradation via the proteasome. DISEASE: Defects in CBL are the cause of Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) [MIM:613563]. A syndrome characterized by a phenotype reminiscent of Noonan syndrome. Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects. MISCELLANEOUS: This protein has one functional calcium-binding site. SIMILARITY: Contains 1 Cbl-PTB (Cbl-type phosphotyrosine-binding) domain. SIMILARITY: Contains 1 RING-type zinc finger. SIMILARITY: Contains 1 UBA domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/CBLID171.html"; GENE SYNONYMS:CBL CBL2 RNF55. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License., SEQUENCE 906 AA; 99633 MW; 1AA6BF67377322CA CRC64;

CBL_HUMAN

urn:biopax:ModificationFeature:CBL_HUMAN_1, urn:biopax:ModificationFeature:CBL_HUMAN_10, urn:biopax:ModificationFeature:CBL_HUMAN_11, urn:biopax:ModificationFeature:CBL_HUMAN_12, urn:biopax:ModificationFeature:CBL_HUMAN_13, urn:biopax:ModificationFeature:CBL_HUMAN_14, urn:biopax:ModificationFeature:CBL_HUMAN_15, urn:biopax:ModificationFeature:CBL_HUMAN_2, urn:biopax:ModificationFeature:CBL_HUMAN_3, urn:biopax:ModificationFeature:CBL_HUMAN_4, urn:biopax:ModificationFeature:CBL_HUMAN_5, urn:biopax:ModificationFeature:CBL_HUMAN_6, urn:biopax:ModificationFeature:CBL_HUMAN_7, urn:biopax:ModificationFeature:CBL_HUMAN_8, urn:biopax:ModificationFeature:CBL_HUMAN_9

MAGNVKKSSGAGGGSGSGGSGSGGLIGLMKDAFQPHHHHHHHLSPHPPGTVDKKMVEKCWKLMDKVVRLCQNPKLALKNSPPYILDLLPDTYQHLRTILSRYEGKMETLGENEYFRVFMENLMKKTKQTISLFKEGKERMYEENSQPRRNLTKLSLIFSHMLAELKGIFPSGLFQGDTFRITKADAAEFWRKAFGEKTIVPWKSFRQALHEVHPISSGLEAMALKSTIDLTCNDYISVFEFDIFTRLFQPWSSLLRNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREGFYLFPDGRNQNPDLTGLCEPTPQDHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPIVVDPFDPRGSGSLLRQGAEGAPSPNYDDDDDERADDTLFMMKELAGAKVERPPSPFSMAPQASLPPVPPRLDLLPQRVCVPSSASALGTASKAASGSLHKDKPLPVPPTLRDLPPPPPPDRPYSVGAESRPQRRPLPCTPGDCPSRDKLPPVPSSRLGDSWLPRPIPKVPVSAPSSSDPWTGRELTNRHSLPFSLPSQMEPRPDVPRLGSTFSLDTSMSMNSSPLVGPECDHPKIKPSSSANAIYSLAARPLPVPKLPPGEQCEGEEDTEYMTPSSRPLRPLDTSQSSRACDCDQQIDSCTYEAMYNIQSQAPSITESSTFGEGNLAAAHANTGPEESENEDDGYDVPKPPVPAVLARRTLSDISNASSSFGWLSLDGDPTTNVTEGSQVPERPPKPFPRRINSERKAGSCQQGSGPAASAATASPQLSSEIENLMSQGYSYQDIQKALVIAQNNIEMAKNILREFVSISSPAHVAT