title: Mutations of c-Cbl in myeloid malignancies.
abstract: Next generation sequencing has shown the frequent occurrence of point mutations in the ubiquitin E3 ligase c-Cbl in myeloid malignancies. Mouse models revealed a causal contribution of c-Cbl for the onset of such neoplasms. The point mutations typically cluster in the linker region and RING finger domain and affect both alleles by acquired uniparental disomy. The fast progress in the detection of c-Cbl mutations is contrasted by our scarce knowledge on their functional consequences. The c-Cbl protein displays several enzymatic functions by promoting the attachment of differentially composed ubiquitin chains and of the ubiquitin-like protein NEDD8 to its target proteins. In addition, c-Cbl functions as an adapter protein and undergoes phosphorylation-dependent inducible conformation changes. Studies on the impact of c-Cbl mutations on its functions as a dynamic and versatile adapter protein, its interactomes and on its various enzymatic activities are now important to allow the identification of druggable targets within the c-Cbl signaling network.
authors.affiliation: Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Shulamit
authors.initials: S
authors.lastname: Katzav
authors.affiliation: Institute of Biochemistry, University of Giessen, Friedrichstrasse, Giessen, Germany.
authors.forename: M Lienhard
authors.initials: ML
authors.lastname: Schmitz
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015195:Drug Design; D020022:Genetic Predisposition to Disease; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human
keywords: cbl; myeloid malignancies