Research Areas

Research in my laboratory focuses on negative regulation of receptor-mediated signaling.  One member of the ErbB receptor family, the epidermal growth factor receptor (EGFR), is negatively regulated by its recruitment of the signaling protein Cbl. Cbl associates with activated EGFR, undergoes tyrosine phosphorylation, and colocalizes with EGFR in tubulovesicular structures of the endocytic pathway.  I and others have shown that overexpression of Cbl enhances EGFR downregulation from the cell surface, recruitment into the endocytic trafficking pathway, and degradation.  Although Cbl functions as a component of the ubiquitylation machinery that targets proteins for proteasome-mediated degradation, the bulk of EGFR degradation occurs in the lysosome.  Studies in my laboratory are aimed at defining the mechanism for Cbl-mediated enhancement of EGFR lysosomal degradation.

Ongoing work addresses the following questions: (1) which Cbl structural domains or motifs are critical for enhanced EGFR downregulation and degradation?; (2) can these domains be used as targeting motifs to degrade other oncogenic receptor tyrosine kinases?; and (3) which protein-protein interactions are required to route activated EGFR to the lysosome, and how are they affected by Cbl overexpression, mutation, or knock-down?  The laboratory utilizes a variety of genetic, biochemical, and cell biological techniques to address these questions.  Exciting ongoing work involves live cell imaging of endocytic fusion events.