title: Regulating the regulator: negative regulation of Cbl ubiquitin ligases.
abstract: Cbl proteins are regulators of signal transduction through many pathways and, consequently, regulate cell function and development. They are ubiquitin ligases that ubiquitinate and target many signaling molecules for degradation. The Cbl proteins themselves are regulated by an increasingly complex network of interactions that fine-tune the effects that Cbl proteins have on signaling. The negative regulation of Cbl protein function can occur via cis-acting structural elements that prevent inappropriate ubiquitin ligase activity, degradation of the Cbl proteins, inhibition without degradation owing to interaction with other signaling proteins, deubiquitination of Cbl substrates, and regulation of assembly of the endosomal ESCRT-I complex. Defects in the regulatory mechanisms that control Cbl function are implicated in the development of immunological and malignant diseases.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Ryan
authors.forename: Gareth C
authors.initials: GC
authors.lastname: Davies
authors.forename: Marion M
authors.initials: MM
authors.lastname: Nau
authors.forename: Stanley
authors.initials: S
authors.lastname: Lipkowitz
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000503:physiopathology; D018106:CD28 Antigens / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology; D051356:Cortactin / Q000502:physiology; D056827:Endosomal Sorting Complexes Required for Transport; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008565:Membrane Proteins; D009369:Neoplasms / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000502:physiology; D009856:Oncogene Proteins, Viral / Q000502:physiology; D017027:Protein Tyrosine Phosphatases; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D018106:CD28 Antigens; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D051356:Cortactin; D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009856:Oncogene Proteins, Viral; D017027:Protein Tyrosine Phosphatases; D050721:Proto-Oncogene Proteins c-cbl; D019009:Proto-Oncogene Proteins c-kit; D044767:Ubiquitin-Protein Ligases; D020764:cdc42 GTP-Binding Protein; D019061:src-Family Kinases; C489394:CLIP4 protein, human; C117020:PDCD6IP protein, human; C404992:Spry2 protein, rat; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins; C489397:UBASH3B protein, human