ID:CBL_HUMAN DESCRIPTION: RecName: Full=E3 ubiquitin-protein ligase CBL; EC=6.3.2.-; AltName: Full=Casitas B-lineage lymphoma proto-oncogene; AltName: Full=Proto-oncogene c-Cbl; AltName: Full=RING finger protein 55; AltName: Full=Signal transduction protein CBL; 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). INTERACTION: P00533:EGFR; NbExp=4; IntAct=EBI-518228, EBI-297353; P55085:F2RL1; NbExp=3; IntAct=EBI-518228, EBI-4303189; P62993:GRB2; NbExp=4; IntAct=EBI-518228, EBI-401755; Q96B97:SH3KBP1; NbExp=2; IntAct=EBI-518228, EBI-346595; 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";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P22681
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
X57110 - Human mRNA for c-cbl proto-oncogene. BC132733 - Homo sapiens Cas-Br-M (murine) ecotropic retroviral transforming sequence, mRNA (cDNA clone MGC:164364 IMAGE:40146755), complete cds. BC136463 - Homo sapiens Cas-Br-M (murine) ecotropic retroviral transforming sequence, mRNA (cDNA clone MGC:168075 IMAGE:9020452), complete cds. JD151343 - Sequence 132367 from Patent EP1572962. CQ873706 - Sequence 125 from Patent WO2004076622. DD413543 - Regulation of Mammalian Cells. DQ575639 - Homo sapiens piRNA piR-43751, complete sequence. X69207 - H.sapiens CBL2 mRNA. JD200043 - Sequence 181067 from Patent EP1572962. JC149583 - Sequence 13 from Patent WO2013148267. JD245392 - Sequence 226416 from Patent EP1572962. DQ577149 - Homo sapiens piRNA piR-45261, complete sequence. DQ571723 - Homo sapiens piRNA piR-31835, complete sequence. DQ592063 - Homo sapiens piRNA piR-59175, complete sequence. BX648139 - Homo sapiens mRNA; cDNA DKFZp686J2246 (from clone DKFZp686J2246). DQ580880 - Homo sapiens piRNA piR-48992, complete sequence. DQ577457 - Homo sapiens piRNA piR-45569, complete sequence. DQ589498 - Homo sapiens piRNA piR-56610, complete sequence. DQ573165 - Homo sapiens piRNA piR-41277, complete sequence. JC149585 - Sequence 15 from Patent WO2013148267. DQ595601 - Homo sapiens piRNA piR-61713, complete sequence. JC149579 - Sequence 9 from Patent WO2013148267. JD429944 - Sequence 410968 from Patent EP1572962. JD420613 - Sequence 401637 from Patent EP1572962. DQ596969 - Homo sapiens piRNA piR-35035, complete sequence. JD380630 - Sequence 361654 from Patent EP1572962. DQ588730 - Homo sapiens piRNA piR-55842, complete sequence. JD090991 - Sequence 72015 from Patent EP1572962. JD224652 - Sequence 205676 from Patent EP1572962. JD498488 - Sequence 479512 from Patent EP1572962. JD409168 - Sequence 390192 from Patent EP1572962. AK092300 - Homo sapiens cDNA FLJ34981 fis, clone OCBBF2000982. AX747463 - Sequence 988 from Patent EP1308459. DQ574133 - Homo sapiens piRNA piR-42245, complete sequence. DQ592796 - Homo sapiens piRNA piR-59908, complete sequence. JD152012 - Sequence 133036 from Patent EP1572962. JD489080 - Sequence 470104 from Patent EP1572962. JD064117 - Sequence 45141 from Patent EP1572962. JD508810 - Sequence 489834 from Patent EP1572962. JD072544 - Sequence 53568 from Patent EP1572962. JD133875 - Sequence 114899 from Patent EP1572962. JD256521 - Sequence 237545 from Patent EP1572962. JD476697 - Sequence 457721 from Patent EP1572962. JD560674 - Sequence 541698 from Patent EP1572962. JD476698 - Sequence 457722 from Patent EP1572962. JD383762 - Sequence 364786 from Patent EP1572962. JD069716 - Sequence 50740 from Patent EP1572962. JD414738 - Sequence 395762 from Patent EP1572962. JD311609 - Sequence 292633 from Patent EP1572962. JD311611 - Sequence 292635 from Patent EP1572962. JD311610 - Sequence 292634 from Patent EP1572962. JD108455 - Sequence 89479 from Patent EP1572962. JD414106 - Sequence 395130 from Patent EP1572962. JD531987 - Sequence 513011 from Patent EP1572962. JD496481 - Sequence 477505 from Patent EP1572962. JD528471 - Sequence 509495 from Patent EP1572962. JD256287 - Sequence 237311 from Patent EP1572962. JD521357 - Sequence 502381 from Patent EP1572962. JD291064 - Sequence 272088 from Patent EP1572962. DQ578084 - Homo sapiens piRNA piR-46196, complete sequence. JD201233 - Sequence 182257 from Patent EP1572962. JD282828 - Sequence 263852 from Patent EP1572962. JD136600 - Sequence 117624 from Patent EP1572962. JD161880 - Sequence 142904 from Patent EP1572962. JD548004 - Sequence 529028 from Patent EP1572962. JD149015 - Sequence 130039 from Patent EP1572962. JD525819 - Sequence 506843 from Patent EP1572962. AL832396 - Homo sapiens mRNA; cDNA DKFZp667M1112 (from clone DKFZp667M1112). DQ576361 - Homo sapiens piRNA piR-44473, complete sequence. JD038257 - Sequence 19281 from Patent EP1572962. JD333438 - Sequence 314462 from Patent EP1572962. JD090101 - Sequence 71125 from Patent EP1572962. JD564815 - Sequence 545839 from Patent EP1572962. JD372425 - Sequence 353449 from Patent EP1572962. JC149587 - Sequence 17 from Patent WO2013148267. JD046657 - Sequence 27681 from Patent EP1572962. JD404989 - Sequence 386013 from Patent EP1572962. JD072713 - Sequence 53737 from Patent EP1572962. JD546481 - Sequence 527505 from Patent EP1572962. JD272207 - Sequence 253231 from Patent EP1572962. JD180652 - Sequence 161676 from Patent EP1572962. JD090049 - Sequence 71073 from Patent EP1572962. JD124749 - Sequence 105773 from Patent EP1572962. JD340205 - Sequence 321229 from Patent EP1572962. JD530266 - Sequence 511290 from Patent EP1572962. JD464467 - Sequence 445491 from Patent EP1572962. JC149581 - Sequence 11 from Patent WO2013148267. JD283138 - Sequence 264162 from Patent EP1572962. JD477620 - Sequence 458644 from Patent EP1572962. JD566646 - Sequence 547670 from Patent EP1572962. JD403640 - Sequence 384664 from Patent EP1572962. DQ579598 - Homo sapiens piRNA piR-47710, complete sequence. DQ583855 - Homo sapiens piRNA piR-50967, complete sequence. MP015247 - Sequence 450 from Patent WO2019016252.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_cblPathway - CBL mediated ligand-induced downregulation of EGF receptors h_spryPathway - Sprouty regulation of tyrosine kinase signals h_il2rbPathway - IL-2 Receptor Beta Chain in T cell Activation
Reactome (by CSHL, EBI, and GO)
Protein P22681 (Reactome details) participates in the following event(s):
R-HSA-1225949 Binding of CBL to ligand-responsive p-6Y-EGFR mutants R-HSA-183052 CBL binds to GRB2 R-HSA-183055 Binding of CBL to EGFR R-HSA-183094 CDC42:GTP binds CBL:Beta-Pix R-HSA-205244 Recruitment of CBL to KIT R-HSA-879917 CBL, GRB2, FYN and PI3K p85 subunit are constitutively associated R-HSA-1112690 PTPN11 binds CBL R-HSA-1295622 SPRY2 binds CBL R-HSA-4332235 CBL binds TGFBR2 R-HSA-8848818 PTK6 phosphorylates CBL R-HSA-1295621 CBL dissociates from ubiquitinated p-SPRY2 R-HSA-4332236 CBL neddylates TGFBR2 R-HSA-912724 CBL binds B-cell linker protein R-HSA-912727 CBL binds VAV R-HSA-912790 CBL binds CRK R-HSA-8848829 CBL autoubiquitinates R-HSA-183067 Localization of CBL:GRB2 to the membrane R-HSA-8876240 CBL binds InlB-activated MET R-HSA-182969 Phosphorylation of CBL (EGFR:CBL) R-HSA-912629 CBL is tyrosine phosphorylated R-HSA-934604 Phosphorylated SPRY2 is ubiquitinated by CBL R-HSA-983703 p-6Y-SYK phosphorylates BLNK (SLP65) R-HSA-1225960 Phosphorylation of CBL by ligand-responsive p-6Y-EGFR mutants R-HSA-8874685 CBL binds MET R-HSA-182986 CBL-mediated ubiquitination of CIN85 R-HSA-183002 Beta-Pix:CDC42:GTP binds CBL in EGF:p-6Y-EGFR:CBL:CIN85 R-HSA-8867044 EGFR binds EPS15, EPN1, EPS15L1 R-HSA-182994 Assembly of EGFR complex in clathrin-coated vesicles R-HSA-183036 Ubiquitination of stimulated EGFR (CBL:GRB2) R-HSA-183058 Phosphorylation of CBL (EGFR:GRB2:CBL) R-HSA-182993 Ubiquitination of stimulated EGFR (CBL) R-HSA-183072 EGFR non-clathrin mediated endocytosis R-HSA-183089 CBL binds and ubiquitinates phosphorylated Sprouty R-HSA-5654673 p-CBL:GRB2 binds p-FRS2:activated FGFR1 R-HSA-5654729 p-CBL:GRB2 binds p-FRS2:activated FGFR2 R-HSA-5654730 p-CBL:GRB2 binds p-FRS2:activated FGFR3 R-HSA-5654734 p-CBL:GRB2 binds p-FRS2:activated FGFR4 R-HSA-912734 CBL:CRKL binds RAPGEF1 R-HSA-183084 CBL escapes CDC42-mediated inhibition by down-regulating the adaptor molecule Beta-Pix R-HSA-8876246 InlB-activated MET phosphorylates CBL R-HSA-183051 CBL ubiquitinates Sprouty R-HSA-8875451 MET phosphorylates CBL R-HSA-8867041 EGFR phosphorylates EPS15 R-HSA-8867047 PTPN3 dephosphorylates EPS15 R-HSA-8951490 CIN85 dissociates from EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP:CIN85 R-HSA-8866279 Epsin family proteins bind ubiquitinated cargo R-HSA-182990 Sprouty sequesters CBL away from active EGFR R-HSA-5654672 CBL ubiquitinates FRS2 and FGFR1 R-HSA-5654677 CBL ubiquitinates FRS2 and FGFR2 R-HSA-5654679 CBL ubiquitinates FRS2 and FGFR3 R-HSA-5654684 CBL ubiquitinates FRS2 and FGFR4 R-HSA-8876258 CBL monoubiquitinates InlB-bound MET R-HSA-8876255 CBL recruits CIN85:endophilin complex to InlB-bound MET R-HSA-8875183 CBL monoubiquitinates activated MET R-HSA-8875482 CBL recruits CIN85:endophilin to ubiquitinated MET R-HSA-8876262 EPS15 and HGS bind CBL-monoubiquitinated MET engaged with Listeria InlB R-HSA-1112666 BLNK (SLP-65) Signalosome hydrolyzes phosphatidyinositol bisphosphate forming diacylglycerol and inositol-1,4,5-trisphosphate R-HSA-8867756 CLASP proteins and cargo are recruited to the nascent clathrin-coated pit R-HSA-8875490 EPS15 and HGS bind ubiquitinated MET R-HSA-8868071 Clathrin recruits PIK3C2A R-HSA-8868661 Dynamin-mediated GTP hydrolysis promotes vesicle scission R-HSA-8868648 SYNJ hydrolyze PI(4,5)P2 to PI(4)P R-HSA-8871194 RAB5 and GAPVD1 bind AP-2 R-HSA-8868658 HSPA8-mediated ATP hydrolysis promotes vesicle uncoating R-HSA-8868659 Clathrin recruits auxilins to the clathrin-coated vesicle R-HSA-8868660 Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle R-HSA-8867754 F- and N- BAR domain proteins bind the clathrin-coated pit R-HSA-8868230 SNX9 recruits components of the actin polymerizing machinery R-HSA-8868072 Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2 R-HSA-8868236 BAR domain proteins recruit dynamin R-HSA-8868651 Endophilins recruit synaptojanins to the clathrin-coated pit R-HSA-1236382 Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants R-HSA-182971 EGFR downregulation R-HSA-1433559 Regulation of KIT signaling R-HSA-912631 Regulation of signaling by CBL R-HSA-1059683 Interleukin-6 signaling R-HSA-1295596 Spry regulation of FGF signaling R-HSA-2173789 TGF-beta receptor signaling activates SMADs R-HSA-5637810 Constitutive Signaling by EGFRvIII R-HSA-8849469 PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 R-HSA-5637815 Signaling by Ligand-Responsive EGFR Variants in Cancer R-HSA-8875360 InlB-mediated entry of Listeria monocytogenes into host cell R-HSA-983695 Antigen activates B Cell Receptor (BCR) leading to generation of second messengers R-HSA-6807004 Negative regulation of MET activity R-HSA-177929 Signaling by EGFR R-HSA-1433557 Signaling by SCF-KIT R-HSA-512988 Interleukin-3, 5 and GM-CSF signaling R-HSA-6783589 Interleukin-6 family signaling R-HSA-5654726 Negative regulation of FGFR1 signaling R-HSA-5654727 Negative regulation of FGFR2 signaling R-HSA-5654732 Negative regulation of FGFR3 signaling R-HSA-5654733 Negative regulation of FGFR4 signaling R-HSA-170834 Signaling by TGF-beta Receptor Complex R-HSA-5637812 Signaling by EGFRvIII in Cancer R-HSA-8848021 Signaling by PTK6 R-HSA-1643713 Signaling by EGFR in Cancer R-HSA-8876384 Listeria monocytogenes entry into host cells R-HSA-983705 Signaling by the B Cell Receptor (BCR) R-HSA-6806834 Signaling by MET R-HSA-9006934 Signaling by Receptor Tyrosine Kinases R-HSA-449147 Signaling by Interleukins R-HSA-5654736 Signaling by FGFR1 R-HSA-5654738 Signaling by FGFR2 R-HSA-5654741 Signaling by FGFR3 R-HSA-5654743 Signaling by FGFR4 R-HSA-9006936 Signaling by TGF-beta family members R-HSA-9006927 Signaling by Non-Receptor Tyrosine Kinases R-HSA-8856825 Cargo recognition for clathrin-mediated endocytosis R-HSA-5663202 Diseases of signal transduction R-HSA-5663205 Infectious disease R-HSA-1280218 Adaptive Immune System R-HSA-162582 Signal Transduction R-HSA-1280215 Cytokine Signaling in Immune system R-HSA-190236 Signaling by FGFR R-HSA-8856828 Clathrin-mediated endocytosis R-HSA-1643685 Disease R-HSA-168256 Immune System R-HSA-199991 Membrane Trafficking R-HSA-5653656 Vesicle-mediated transport
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
