Mutations of c-Cbl in myeloid malignancies

Shulamit Katzav _ and M. Lienhard Schmitz

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Oncotarget. 2015; 6:10689-10696. https://doi.org/10.18632/oncotarget.3986

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Shulamit Katzav1 and M. Lienhard Schmitz2

1 Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel

2 Institute of Biochemistry, University of Giessen, Friedrichstrasse, Giessen, Germany

Correspondence to:

Shulamit Katzav, email:

M. Lienhard Schmitz, email:

Keywords: cbl, myeloid malignancies

Received: March 03, 2015 Accepted: April 15, 2015 Published: May 04, 2015


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.

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