Lochan Shah Rose Hills
The Structural Basis of Cbl Specificity
The protein Cbl is a key component of receptor tyrosine kinase transduction, acting both as an E3 ligase and as an adaptor in the ubiquitination pathway. In fact, overexpression of Cbl has been found to inhibit tumor growth; therefore, understanding Cbls specificity will be key to the development of relevant therapeutic drugs. Interestingly, Cbl is known to ubiquitylate over one dozen targets, and its specificity for tyrosine kinases is achieved by its unique activation mechanism. Recent work has found that Cbl recognizes multiple lysine residues from the same substrate and certain lysines appear to be targeted for ubiquitination. However, no mechanism has been developed to explain how this occurs. This summer, I will be investigating the molecular basis of the selectivity of Cbl on protein tyrosine kinases. To address this question, I will use structural biology and biochemistry; specifically, I will express and purify various versions of Cbl substrates, perform ubiquitylation assays, and analyze lysine modifications via mass spectrometry.