The Epidermal growth factor receptor (EGFR) plays key roles in oncogenesis, cell proliferation, survival, migration and differentiation. Regulation of EGFR protein levels and signaling is critical; clathrin-mediated endocytosis and subsequent lysosomal degradation of internalized EGF-receptor complexes is one mechanism of regulating the EGFR. A number of proteins have been implicated in EGFR endocytosis but the identity of the protein(s) that recruit EGFR to clathrin-coated pits is unknown. I hypothesize that Disabled- 2 (Dab2) may provide a mechanism by which EGFR is recruited to clathrin-coated pits. Dab2, an adaptor protein that binds to a number of endocytic proteins, is known to be involved in endocytosis of Megalin, Cubilin and ApoER2 receptors. Dab2 expression is strongly inhibited in several types of cancers and rexpression of Dab2 in cancer lines inhibits their growth. We have seen an increase in cell surface EGFR in cells depleted of Dab2 and ARM,another endocytic adaptor. In this study, I propose to determine whether and how Dab2 regulates EGFR endocytosis. Regulation of EGFR protein levels by Dab2 maybe a mechanism by which Dab2 suppresses tumor growth.
| Teckchandani, Anjali; Toida, Natalie; Goodchild, Jake et al. (2009) Quantitative proteomics identifies a Dab2/integrin module regulating cell migration. J Cell Biol 186:99-111 |
