Abstract: Award DAMD-99-l-9367 seeks to understand the role of membrane trafficking in Epidermal Growth Factor Receptor (EGER) signal transduction. We have been using a tissue culture model system (HeLa cells) to isolate the activated EGER at distinct stages in the endocytic pathway. Our research has focused on rab5, a small molecular weight GTPase, implicated in the biogenesis of the early endosome. Mutations to modulate the guanine nucleotide binding properties of this protein have been reported for constitutively internalized receptors, but little is known about its role in EGFR endocytic trafficking. In the past year, we have discovered that expression of a dominant negative' rab5 (rab5(S34N)), has no effect on EGFR endocytosis, but inhibits entry of the EGFR into the early endosome. The functional consequence of this mutation is slowed rate of EGER degradation. Additionally, we have found that the guanine nucleotide binding state of the rab5 proteins dictates the ability of the cells to mediate EGER- dependent cell growth. Cells expressing rab5 that preferentially bindings GDP growth significantly better than cells expressing rab5 that binds GTP.
| Limitations: |
 APPROVED FOR PUBLIC RELEASE |
| Description: |
Annual rept. 1 Jul 1999-30 Jun 2002 |
| Pages: |
68 |
| Report Date: |
JUL 2002 |
| Contract Number: |
DAMD179919367 |
| Report Number: |
B220482 |
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