BioPAX pathway converted from "CBL ubiquitinates PI3K" in the Reactome database.CBL ubiquitinates PI3KCBL ubiquitinates PI3KCbl is an E3 ubiquitin-protein ligase that negatively regulates signaling pathways by targeting proteins for ubiquitination and proteasomal degradation (Rao et al. 2002). Cbl-B targets PI3K for ubiquitination and degradation in T cells (Fang et al. 2000). Similarly, Cbl activation by tyrosine phosphorylation increases PI3K ubiquitination and proteasomal degradation (Dufour et al. 2008).Authored: Ray, KP, 2010-05-17Reviewed: Lopez, AF, 2010-09-06Reviewed: Hercus, TR, 2010-09-06Edited: Jupe, S, 2010-08-06Reactome DB_ID: 9127401cytosolGO0005829K48polyUb [cytosol]K48polyUbLys-48 polyubiquitinK48-polyubiquitinReactomehttp://www.reactome.orgReactome DB_ID: 9126471FYN-like kinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3Ks [cytosol]FYN-like kinases:p(Y731)-CBL:GRB2:p85-containing Class 1A PI3KsReactome DB_ID: 9126561UniProt:P22681 CBLCBLRNF55CBL2CBLFUNCTION 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, SRC 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. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. In association with CBLB, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Forms homodimers; IFT20 promotes the formation of stable homodimers (PubMed:29237719). 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 (By similarity). Interacts with CBLB (PubMed:29237719). 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). Interacts with SH3KBP1 and this interaction is inhibited in the presence of SHKBP1 (By similarity). Interacts with SIGLEC10 (By similarity). Interacts with IFT20 (PubMed:29237719).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 (PubMed:11896602, PubMed:20094046). Ubiquitination is negatively regulated by IFT20 (PubMed:29237719).MISCELLANEOUS This protein has one functional calcium-binding site.Homo sapiensNCBI Taxonomy9606UniProtP22681O4'-phospho-L-tyrosine at 731731EQUALO4'-phospho-L-tyrosine [MOD:00048]O4'-phospho-L-tyrosine at 700700EQUALO4'-phospho-L-tyrosine at 774774EQUALChain Coordinates1EQUAL906EQUALConverted from EntitySet in ReactomeReactome DB_ID: 9126251FYN-like kinases [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityFYN [cytosol]UniProtP06241Reactome DB_ID: 746861UniProt:P62993-1 GRB2GRB2ASHGRB2FUNCTION Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.FUNCTION Isoform 2 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform 2 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death.SUBUNIT Associates (via SH2 domain) with activated EGF and PDGF receptors (tyrosine phosphorylated) (PubMed:10026169, PubMed:19836242). Interacts with PDGFRA (tyrosine phosphorylated); the interaction may be indirect (By similarity). Also associates to other cellular Tyr-phosphorylated proteins such as SIT1, IRS1, IRS4, SHC and LNK; probably via the concerted action of both its SH2 and SH3 domains (PubMed:8388384, PubMed:8491186, PubMed:9553137, PubMed:11433379). It also seems to interact with RAS in the signaling pathway leading to DNA synthesis. Interacts with SOS1 (PubMed:8493579, PubMed:7664271). Forms a complex with MUC1 and SOS1, through interaction of the SH3 domains with SOS1 and the SH2 domain with phosphorylated MUC1 (PubMed:7664271). Interacts with phosphorylated MET (PubMed:11063574, PubMed:11827484). Interacts with phosphorylated TOM1L1 (By similarity). Interacts with the phosphorylated C-terminus of SH2B2 (PubMed:9233773). Interacts with phosphorylated SIT1, LAX1, LAT, LAT2 and LIME1 upon TCR and/or BCR activation (By similarity) (PubMed:9489702, PubMed:12359715, PubMed:12486104, PubMed:12514734). Interacts with NISCH, PTPNS1 and REPS2 (PubMed:9062191, PubMed:9422736, PubMed:11912194). Interacts with syntrophin SNTA1 (By similarity). Interacts (via SH3 domains) with REPS1 (By similarity). Interacts (via SH3 domains) with PIK3C2B (PubMed:11533253). Interacts with CBL and CBLB (PubMed:10022120, PubMed:10086340). Interacts with AJUBA and CLNK (By similarity). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (By similarity). Interacts with SHB, INPP5D/SHIP1, SKAP1 and SKAP2 (PubMed:8723348, PubMed:9108392, PubMed:9484780, PubMed:10942756, PubMed:12171928). Interacts with PTPN11 (By similarity). Interacts with PRNP (By similarity). Interacts with RALGPS1 (PubMed:10747847). Interacts with HCST (PubMed:16582911). Interacts with KDR (By similarity). Interacts with FLT1 (tyrosine-phosphorylated) (By similarity). Interacts with GAPT and PTPRE (PubMed:10980613, PubMed:18559951). Interacts (via SH2 domain) with KIF26A (PubMed:19914172). Interacts (via SH3 2) with GAB2 (PubMed:19523899). Interacts with ADAM15 (PubMed:18296648). Interacts with THEMIS2 (By similarity). Interacts (via SH2 domain) with AXL (phosphorylated) (PubMed:9178760, PubMed:19815557). Interacts (via SH2 domain) with KIT (phosphorylated) (PubMed:15526160, PubMed:16129412). Interacts with PTPRJ and BCR (PubMed:12475979, PubMed:15302586). Interacts with PTPN23 (PubMed:21179510). Interacts with FLT4 (tyrosine phosphorylated) (PubMed:15102829). Interacts with EPHB1 and SHC1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:8798570, PubMed:12925710). Part of a complex including TNK2, GRB2, LTK and one receptor tyrosine kinase (RTK) such as AXL and PDGFRL, in which GRB2 promotes RTK recruitment by TNK2 (PubMed:9178760, PubMed:19815557). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (PubMed:8262059). Interacts with ERBB4 (PubMed:10867024). Interacts with NTRK1 (phosphorylated upon ligand-binding) (PubMed:15488758). Interacts with PTK2/FAK1 (tyrosine phosphorylated) (PubMed:9148935). Interacts with PTK2B/PYK2 (tyrosine phosphorylated) (PubMed:20521079). Isoform 1: Interacts (via SH2-domain) with SCIMP; this interaction is dependent on phosphorylation of SCIMP 'Tyr-69' (PubMed:21930792). Interacts (via SH3 domains) with GAREM1 isoform 1 (via proline-rich domain and tyrosine phosphorylated); the interaction occurs upon EGF stimulation (PubMed:19509291). Interacts with DAB2 (By similarity). Interacts with TESPA1 (PubMed:22561606). Interacts with PLCG1, LAT and THEMIS upon TCR activation in thymocytes; the association is weaker in the absence of TESPA1 (By similarity). Interacts with CD28 (PubMed:24098653). Interacts with RAB13; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA (By similarity). Interacts with ASAP3 (phosphorylated form) (PubMed:22027826). Interacts (via SH2 domain) with PTPRH (phosphorylated form) (By similarity). Interacts with PTPRO (phosphorylated form) (By similarity). Interacts with PTPRB (phosphorylated form) (By similarity). Interacts (via SH3 domain 2) with PRR14 (via proline-rich region) (PubMed:27041574). Interacts with FCRL6 (tyrosine phosphorylated form) (PubMed:20933011). Interacts with RHEX (via tyrosine-phosphorylated form) (PubMed:25092874). Interacts with DENND2B (PubMed:29030480). Interacts (via SH3 domain) with ZDHHC19 (via SH3-binding motif); leading to recruit STAT3 (PubMed:31462771).SUBUNIT (Microbial infection) Interacts (via SH3 domain) with hepatitis E virus/HEV ORF3 protein.SUBUNIT (Microbial infection) Interacts with hepatitis C virus/HCV protein NS5A via its SH3 domains.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL46.DOMAIN The SH3 domains mediate interaction with RALGPS1 and SHB.SIMILARITY Belongs to the GRB2/sem-5/DRK family.UniProtP62993-11EQUAL217EQUALConverted from EntitySet in ReactomeReactome DB_ID: 5082481p85-containing Class 1A PI3Ks [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome Database ID Release 73912647Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=912647ReactomeR-HSA-9126471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-912647.1Reactome DB_ID: 9127991FYN-like kinases:p(Y731)-CBL:GRB2:Ubiquitinated p85-containing Class 1A PI3Ks [cytosol]FYN-like kinases:p(Y731)-CBL:GRB2:Ubiquitinated p85-containing Class 1A PI3KsConverted from EntitySet in ReactomeReactome DB_ID: 30805531K63polyUb-p85-containing Class 1A PI3Ks [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome DB_ID: 9126561O4'-phospho-L-tyrosine at 731731EQUALO4'-phospho-L-tyrosine at 700700EQUALO4'-phospho-L-tyrosine at 774774EQUAL1EQUAL906EQUALConverted from EntitySet in ReactomeReactome DB_ID: 9126251Reactome DB_ID: 7468611EQUAL217EQUALReactome Database ID Release 73912799Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=912799ReactomeR-HSA-9127991Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-912799.1Reactome Database ID Release 73912627Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=912627ReactomeR-HSA-9126271Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-912627.111087752Pubmed2001Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cellsFang, DWang, HYFang, NAltman, YElly, CLiu, YCJ Biol Chem 276:4872-811994499Pubmed2002The Cbl family of ubiquitin ligases: critical negative regulators of tyrosine kinase signaling in the immune systemRao, NDodge, IBand, HJ Leukoc Biol 71:753-6318374639Pubmed2008FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survivalDufour, CGuenou, HKaabeche, KBouvard, DSanjay, AMarie, PJBone 42:1032-9