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Frontiers in Mathematical Oncology

Oncogenic Mutations in Cbl Proteins

Stan Lipkowitz

National Institutes of Health


Dysregulated activity of receptor tyrosine kinases (RTKs) by amplification and/or activating mutations has been shown to play a role in many human cancers.  The Cbl proteins are a family of RING Finger ubiquitin ligases (E3s) which ubiquitinate and down regulate activated RTKs and thus they normally serve to attenuate signaling by RTKs.  Mutations of Cbl have been identified in approximately 5%of myeloid neoplasms and more recently a low frequency of mutations in Cbl proteins have been identified in human epithelial malignancies.  Most of the mutations that have been identified in the Cbl proteins inactivate the E3 catalytic activity however the proteins can still bind to their RTK targets.  The mutated forms of Cbl act as dominant negative proteins which block the interaction of the remaining wild type Cbl proteins with the RTK.  This leads to a failure to down regulate the activated RTKs and an increase in RTK signaling.  Thus, the mutations in the Cbl proteins are another means to dysregulate RTK signaling leading to malignant transformation. This is joint work with Anna Panchenko at NCBI.