The Cbl interactome and its functions

Cbl proteins are ubiquitin ligases and multifunctional adaptor proteins that are implicated in the regulation of signal transduction in various cell types and in response to different stimuli. Cbl-associated proteins can assemble together at a given time or space inside the cell, and such an interactome can form signal competent networks that control many physiological processes. Dysregulation of spatial or temporal constraints in the Cbl interactome results in the development of human pathologies such as immune diseases, diabetes and cancer.

[1]  Jean Gruenberg,et al.  The biogenesis of multivesicular endosomes , 2004, Nature Reviews Molecular Cell Biology.

[2]  P. De Camilli,et al.  CIN85 associates with multiple effectors controlling intracellular trafficking of epidermal growth factor receptors. , 2004, Molecular biology of the cell.

[3]  D. Bowtell,et al.  The protein product of the c-cbl oncogene rapidly complexes with the EGF receptor and is tyrosine phosphorylated following EGF stimulation. , 1995, Oncogene.

[4]  Xuejun Jiang,et al.  Grb2 regulates internalization of EGF receptors through clathrin-coated pits. , 2003, Molecular biology of the cell.

[5]  P. Soubeyran,et al.  Cbl signaling networks in the regulation of cell function , 2003, Cellular and Molecular Life Sciences CMLS.

[6]  B. Rellahan,et al.  70Z/3 Cbl induces PLCγ1 activation in T lymphocytes via an alternate Lat- and Slp-76-independent signaling mechanism , 2003, Oncogene.

[7]  M. Kanzaki,et al.  Insulin-stimulated GLUT4 Translocation in Adipocytes Is Dependent upon Cortical Actin Remodeling* 210 , 2001, The Journal of Biological Chemistry.

[8]  W. Langdon.  The cbl oncogene: a novel substrate of protein tyrosine kinases. , 1995, Australian and New Zealand journal of medicine.

[9]  Arup K Chakraborty,et al.  The Immunological Synapse Balances T Cell Receptor Signaling and Degradation , 2003, Science.

[10]  R. Irvine.  Nuclear lipid signalling , 2003, Nature Reviews Molecular Cell Biology.

[11]  S. Hanks,et al.  Complexes of Focal Adhesion Kinase (FAK) and Crk-associated Substrate (p130Cas) Are Elevated in Cytoskeleton-associated Fractions following Adhesion and Src Transformation , 1997, The Journal of Biological Chemistry.

[12]  Lei Duan,et al.  Cbl-mediated Ubiquitinylation and Negative Regulation of Vav* , 2003, Journal of Biological Chemistry.

[13]  H. Stenmark.  Membrane traffic: Cycling lipids , 2000, Current Biology.

[14]  M. E. Cook,et al.  Regulation of β1-integrin-mediated cell adhesion by the CbI adaptor protein , 1998, Current Biology.

[15]  G. Corthals,et al.  A Cortactin-CD2-associated Protein (CD2AP) Complex Provides a Novel Link between Epidermal Growth Factor Receptor Endocytosis and the Actin Cytoskeleton* , 2003, Journal of Biological Chemistry.

[16]  A. Ullrich,et al.  All autophosphorylation sites of epidermal growth factor (EGF) receptor and HER2/neu are located in their carboxyl-terminal tails. Identification of a novel site in EGF receptor. , 1989, The Journal of biological chemistry.

[17]  C. Elly,et al.  Cbl Promotes Ubiquitination of the T Cell Receptor ζ through an Adaptor Function of Zap-70* , 2001, The Journal of Biological Chemistry.

[18]  K. Robbins,et al.  Cloning and characterization of cbl-b: a SH3 binding protein with homology to the c-cbl proto-oncogene. , 1995, Oncogene.

[19]  Aaron Ciechanover,et al.  Proteolysis: from the lysosome to ubiquitin and the proteasome , 2005, Nature Reviews Molecular Cell Biology.

[20]  S. Fang,et al.  WW Domain HECT E3s Target Cbl RING Finger E3s for Proteasomal Degradation* , 2003, Journal of Biological Chemistry.

[21]  I. Madshus,et al.  Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation. , 2004, Experimental cell research.

[22]  Linda Hicke,et al.  Ubiquitin and proteasomes: Protein regulation by monoubiquitin , 2001, Nature Reviews Molecular Cell Biology.

[23]  F. Alt,et al.  Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. , 2000, Immunity.

[24]  J. Chang,et al.  SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[25]  S. Lipkowitz,et al.  Serine Phosphorylation of Cbl Induced by Phorbol Ester Enhances Its Association with 14-3-3 Proteins in T Cells via a Novel Serine-rich 14-3-3-binding Motif* , 1997, The Journal of Biological Chemistry.

[26]  C. Elly,et al.  Protein kinase C activation inhibits tyrosine phosphorylation of Cbl and its recruitment of Src homology 2 domain-containing proteins. , 1999, Journal of immunology.

[27]  H. Band,et al.  Phosphotyrosine binding domain-dependent upregulation of the platelet-derived growth factor receptor alpha signaling cascade by transforming mutants of Cbl: implications for Cbl's function and oncogenicity , 1997, Molecular and cellular biology.

[28]  Sakae Tanaka,et al.  Tyrosine Phosphorylation and Translocation of the c-Cbl Protein after Activation of Tyrosine Kinase Signaling Pathways (*) , 1995, The Journal of Biological Chemistry.

[29]  P. Sternberg,et al.  sli-1, a negative regulator of let-23-mediated signaling in C. elegans. , 1995, Genetics.

[30]  D. Mueller.  E3 ubiquitin ligases as T cell anergy factors , 2004, Nature Immunology.

[31]  R. Baron,et al.  Src-catalyzed Phosphorylation of c-Cbl Leads to the Interdependent Ubiquitination of Both Proteins* , 2001, The Journal of Biological Chemistry.

[32]  T. Kurosaki,et al.  Cbl Suppresses B Cell Receptor–Mediated Phospholipase C (Plc)-γ2 Activation by Regulating B Cell Linker Protein–Plc-γ2 Binding , 2000, The Journal of experimental medicine.

[33]  R. Salgia,et al.  p210BCR/ABL induces formation of complexes containing focal adhesion proteins and the protooncogene product p120c-Cbl. , 1996, Experimental hematology.

[34]  P. Sternberg,et al.  Similarity of sli-1, a regulator of vulval development in C. elegans, to the mammalian proto-oncogene c-cbl , 1995, Science.

[35]  D. Bowtell,et al.  A Mouse with a Loss-of-function Mutation in the c-Cbl TKB Domain Shows Perturbed Thymocyte Signaling without Enhancing the Activity of the ZAP-70 Tyrosine Kinase , 2003, The Journal of experimental medicine.

[36]  I. Dikic,et al.  Receptor endocytosis via ubiquitin-dependent and -independent pathways. , 2004, Biochemical pharmacology.

[37]  T. Kurosaki,et al.  Distinct tyrosine phosphorylation sites in ZAP-70 mediate activation and negative regulation of antigen receptor function , 1996, Molecular and cellular biology.

[38]  R. Geahlen,et al.  Phosphorylation- and Activation-independent Association of the Tyrosine Kinase Syk and the Tyrosine Kinase Substrates Cbl and Vav with Tubulin in B-Cells* , 1999, The Journal of Biological Chemistry.

[39]  T. Yagi,et al.  Physical and functional association of the cbl protooncogen product with an src-family protein tyrosine kinase, p53/56lyn, in the B cell antigen receptor-mediated signaling , 1996, The Journal of experimental medicine.

[40]  C. Pickart,et al.  Mechanisms underlying ubiquitination. , 2001, Annual review of biochemistry.

[41]  W. Langdon,et al.  The multi-adaptor proto-oncoprotein Cbl is a key regulator of Rac and actin assembly , 2003, Journal of Cell Science.

[42]  W. Langdon,et al.  Fyn, Yes, and Syk Phosphorylation Sites in c-Cbl Map to the Same Tyrosine Residues That Become Phosphorylated in Activated T Cells* , 1998, The Journal of Biological Chemistry.

[43]  S. Pierce,et al.  Cbl-b Negatively Regulates B Cell Antigen Receptor Signaling in Mature B Cells through Ubiquitination of the Tyrosine Kinase Syk , 2003, The Journal of experimental medicine.

[44]  Tobias Meyer,et al.  Phosphatidylinositol 4,5-Bisphosphate Functions as a Second Messenger that Regulates Cytoskeleton–Plasma Membrane Adhesion , 2000, Cell.

[45]  D. Bar-Sagi,et al.  Modulation of signalling by Sprouty: a developing story , 2004, Nature Reviews Molecular Cell Biology.

[46]  M. Sajan,et al.  Requirements for pYXXM motifs in Cbl for binding to the p85 subunit of phosphatidylinositol 3-kinase and Crk, and activation of atypical protein kinase C and glucose transport during insulin action in 3T3/L1 adipocytes. , 2004, Biochemistry.

[47]  P. Doherty,et al.  Regulation of ZAP-70 activation and TCR signaling by two related proteins, Sts-1 and Sts-2. , 2004, Immunity.

[48]  J. Schlessinger.  Cell Signaling by Receptor Tyrosine Kinases , 2000, Cell.

[49]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[50]  Y. Yarden,et al.  Src promotes destruction of c-Cbl: Implications for oncogenic synergy between Src and growth factor receptors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[51]  S. Emr,et al.  The role of phosphoinositides in membrane transport. , 2001, Current opinion in cell biology.

[52]  C. Elly,et al.  Cbl-b, a RING-type E3 Ubiquitin Ligase, Targets Phosphatidylinositol 3-Kinase for Ubiquitination in T Cells* , 2001, The Journal of Biological Chemistry.

[53]  D. Bowtell,et al.  Cbl Associates with Pyk2 and Src to Regulate Src Kinase Activity, αvβ3 Integrin-Mediated Signaling, Cell Adhesion, and Osteoclast Motility , 2001, The Journal of cell biology.

[54]  V. Band,et al.  Tyrosine Phosphorylation of Cbl upon Epidermal Growth Factor (EGF) Stimulation and Its Association with EGF Receptor and Downstream Signaling Proteins* , 1996, The Journal of Biological Chemistry.

[55]  A. Saltiel,et al.  APS Facilitates c-Cbl Tyrosine Phosphorylation and GLUT4 Translocation in Response to Insulin in 3T3-L1 Adipocytes , 2002, Molecular and Cellular Biology.

[56]  S. Kajigaya,et al.  Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes. , 2000, Biochemical and biophysical research communications.

[57]  B. Kay,et al.  A Role for CAP, a Novel, Multifunctional Src Homology 3 Domain-containing Protein in Formation of Actin Stress Fibers and Focal Adhesions* , 1998, The Journal of Biological Chemistry.

[58]  H. Nishina,et al.  Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b , 2000, Nature.

[59]  J. Schlessinger,et al.  Tyrosine Phosphorylation of the c-cbl Proto-oncogene Protein Product and Association with Epidermal Growth Factor (EGF) Receptor upon EGF Stimulation (*) , 1995, The Journal of Biological Chemistry.

[60]  H. Band,et al.  The non‐receptor tyrosine kinase Syk is a target of Cbl‐mediated ubiquitylation upon B‐cell receptor stimulation , 2001, The EMBO journal.

[61]  Ivan Dikic,et al.  Negative receptor signalling. , 2003, Current opinion in cell biology.

[62]  D. Durden,et al.  SLP-76-Cbl-Grb 2-Shc Interactions in Fc g RI Signaling , 1998 .

[63]  M. Nau,et al.  Cbl-b interacts with ubiquitinated proteins; differential functions of the UBA domains of c-Cbl and Cbl-b , 2004, Oncogene.

[64]  Joseph Schlessinger,et al.  Ligand-Induced, Receptor-Mediated Dimerization and Activation of EGF Receptor , 2002, Cell.

[65]  R. Salgia,et al.  Tyrosine phosphorylation of the product of the c-cbl protooncogene is [corrected] induced after integrin stimulation. , 1997, Experimental hematology.

[66]  K. Hofmann,et al.  When ubiquitin meets ubiquitin receptors: a signalling connection , 2003, Nature Reviews Molecular Cell Biology.

[67]  P. Sternberg,et al.  LET‐23‐mediated signal transduction during Caenorhabditis elegans development , 1995, Molecular reproduction and development.

[68]  E. Shevach,et al.  Cbl-b regulates the CD28 dependence of T-cell activation , 2000, Nature.

[69]  S. Sugano,et al.  Molecular cloning and characterization of a novel cbl-family gene, cbl-c. , 1999, Gene.

[70]  M. Matsuda,et al.  Activation of R-Ras by Ras-Guanine Nucleotide-releasing Factor* , 1997, The Journal of Biological Chemistry.

[71]  L. B. Drobot,et al.  Negative regulation of PI 3‐kinase by Ruk, a novel adaptor protein , 2000, The EMBO journal.

[72]  Mirko H. H. Schmidt,et al.  SETA/CIN85/Ruk and its binding partner AIP1 associate with diverse cytoskeletal elements, including FAKs, and modulate cell adhesion , 2003, Journal of Cell Science.

[73]  Makoto Kanzaki,et al.  Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10 , 2001, Nature.

[74]  W. Cavenee,et al.  Alix/AIP1 Antagonizes Epidermal Growth Factor Receptor Downregulation by the Cbl-SETA/CIN85 Complex , 2004, Molecular and Cellular Biology.

[75]  D. Bowtell,et al.  Tissue Hyperplasia and Enhanced T-Cell Signalling via ZAP-70 in c-Cbl-Deficient Mice , 1998, Molecular and Cellular Biology.

[76]  H. Stenmark.  Cycling lipids. , 2000, Current biology : CB.

[77]  W. Langdon,et al.  c-Cbl localizes to actin lamellae and regulates lamellipodia formation and cell morphology. , 2000, Journal of cell science.

[78]  M. Frame,et al.  Newest findings on the oldest oncogene; how activated src does it , 2004, Journal of Cell Science.

[79]  Sakae Tanaka,et al.  c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption , 1996, Nature.

[80]  T. Kurosaki,et al.  Cbl-b Positively Regulates Btk-mediated Activation of Phospholipase C-γ2 in B Cells , 2002, The Journal of experimental medicine.

[81]  M. Czech,et al.  Coupling of the Proto-oncogene Product c-Cbl to the Epidermal Growth Factor Receptor (*) , 1995, The Journal of Biological Chemistry.

[82]  J. Penninger,et al.  cbl-3: a new mammalian cbl family protein , 1999, Oncogene.

[83]  Mike Tyers,et al.  The GRID: The General Repository for Interaction Datasets , 2003, Genome Biology.

[84]  I. Amit,et al.  Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding. , 2004, Genes & development.

[85]  W. Langdon,et al.  Rapid microtubule-dependent induction of neurite-like extensions in NIH 3T3 fibroblasts by inhibition of ROCK and Cbl. , 2003, Molecular biology of the cell.

[86]  R. Irvine.  20 years of Ins(1,4,5)P3, and 40 years before , 2003, Nature Reviews Molecular Cell Biology.

[87]  J. Penninger,et al.  Molecular controls of antigen receptor clustering and autoimmunity. , 2001, Trends in cell biology.

[88]  L. Platanias,et al.  Interaction of the c-cbl proto-oncogene product with the Tyk-2 protein tyrosine kinase. , 1996, Biochemical and biophysical research communications.

[89]  I. Dikic,et al.  Cbl–CIN85–endophilin complex mediates ligand-induced downregulation of EGF receptors , 2002, Nature.

[90]  K. Vuori,et al.  The Proto-oncogene Product p120cbl Links c-Src and Phosphatidylinositol 3′-Kinase to the Integrin Signaling Pathway* , 1997, The Journal of Biological Chemistry.

[91]  Giorgio F. Gilestro,et al.  The endophilin–CIN85–Cbl complex mediates ligand-dependent downregulation of c-Met , 2002, Nature.

[92]  M. Tyers,et al.  Osprey: a network visualization system , 2003, Genome Biology.

[93]  W. Cavenee,et al.  Epidermal growth factor receptor signaling intensity determines intracellular protein interactions, ubiquitination, and internalization , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[94]  R. Cerione,et al.  Activated Cdc42 Sequesters c-Cbl and Prevents EGF Receptor Degradation , 2003, Cell.

[95]  I. Dikic,et al.  Cbl-ArgBP2 complex mediates ubiquitination and degradation of c-Abl. , 2003, The Biochemical journal.

[96]  S. Ryu,et al.  Cbl competitively inhibits epidermal growth factor-induced activation of phospholipase C-gamma1. , 2003, Molecules and cells.

[97]  T. Hunter,et al.  The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. , 1999, Science.

[98]  P. Transidico,et al.  Clathrin-independent endocytosis of ubiquitinated cargos. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[99]  W. Langdon,et al.  Cbl: many adaptations to regulate protein tyrosine kinases , 2001, Nature Reviews Molecular Cell Biology.

[100]  C. Goodnow,et al.  Scaffolding of antigen receptors for immunogenic versus tolerogenic signaling , 2003, Nature Immunology.

[101]  C. Heldin,et al.  Suppressors of T-cell Receptor Signaling Sts-1 and Sts-2 Bind to Cbl and Inhibit Endocytosis of Receptor Tyrosine Kinases* , 2004, Journal of Biological Chemistry.

[102]  M. Naramura,et al.  Altered thymic positive selection and intracellular signals in Cbl-deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[103]  R. Iyengar,et al.  Signaling Networks The Origins of Cellular Multitasking , 2000, Cell.

[104]  I. Dikic,et al.  Compartmentalization of growth factor receptor signalling. , 2005, Current opinion in cell biology.

[105]  I. Dikic,et al.  Src Phosphorylation of Alix/AIP1 Modulates Its Interaction with Binding Partners and Antagonizes Its Activities* , 2005, Journal of Biological Chemistry.

[106]  J. Penninger,et al.  Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. , 2004, Immunity.

[107]  A Ciechanover,et al.  Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. , 1999, Molecular cell.

[108]  M. Deckert,et al.  Coordinated Regulation of the Tyrosine Phosphorylation of Cbl by Fyn and Syk Tyrosine Kinases* , 1998, The Journal of Biological Chemistry.

[109]  Y. Yarden,et al.  Coupling of the c-Cbl protooncogene product to ErbB-1/EGF-receptor but not to other ErbB proteins. , 1996, Oncogene.

[110]  I. Dikic,et al.  CIN85/CMS family of adaptor molecules , 2002, FEBS letters.

[111]  I. Dikic,et al.  Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation , 2005, EMBO reports.

[112]  R. Birge,et al.  The Adapter Type Protein CMS/CD2AP Binds to the Proto-oncogenic Protein c-Cbl through a Tyrosine Phosphorylation-regulated Src Homology 3 Domain Interaction* , 2001, The Journal of Biological Chemistry.

[113]  M. Naramura,et al.  c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation , 2002, Nature Immunology.

[114]  Marino Zerial,et al.  Rab proteins as membrane organizers , 2001, Nature Reviews Molecular Cell Biology.

[115]  C. Lowell,et al.  A β1 integrin signaling pathway involving Src‐family kinases, Cbl and PI‐3 kinase is required for macrophage spreading and migration , 1998, The EMBO journal.

[116]  G. Kruh,et al.  Recruitment of Pyk2 and Cbl to lipid rafts mediates signals important for actin reorganization in growing neurites , 2004, Journal of Cell Science.

[117]  R. Khokha,et al.  Cbl-3-Deficient Mice Exhibit Normal Epithelial Development , 2003, Molecular and Cellular Biology.

[118]  E. Janssen,et al.  Adaptor proteins in lymphocyte activation. , 2003, Current opinion in immunology.

[119]  A. Calistri,et al.  AIP1/ALIX Is a Binding Partner for HIV-1 p6 and EIAV p9 Functioning in Virus Budding , 2003, Cell.

[120]  S. Carr,et al.  TULA: an SH3- and UBA-containing protein that binds to c-Cbl and ubiquitin , 2004, Oncogene.

[121]  Rick A. Rogers,et al.  Cbl-mediated Ubiquitinylation Is Required for Lysosomal Sorting of Epidermal Growth Factor Receptor but Is Dispensable for Endocytosis* , 2003, Journal of Biological Chemistry.

[122]  S. Klinken,et al.  v-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas. , 1989, Proceedings of the National Academy of Sciences of the United States of America.