Functional Interactions Between c-Src and HER1 Potentiate Neoplastic Transformation: Implications for the Etiology of Human Breast Cancer.
Abstract
Interactions between HER1 and c-Src may contribute to a more aggressive phenotype in human breast cancer. Previous work from our laboratory has demonstrated that c-Src and HER1 may interact synergistically in a fibroblast model system to potentiate transformation. Here, I show that HER1 was overexpressed in 5/14 human breast cancer cell lines examined, and this overexpression correlated with an EGF-dependent physical association between HERl and c-Src. These findings also correlate with increases in phosphorylation of the HERl substrate She and activation of its downstream effector MAPK, with respect to cells that did not overexpress HER1; and with increased tumorigenicity in nude mice. In a mouse fibroblast model system, and in MDA468 breast cancer cells, HERl in association with c-Src became phosphorylated on two novel sites: Tyr84S and Tyri 1101. Phosphorylation of Tyr 845 was not observed in cells expressing kinase inactive c-Src, suggesting that this site is a target for the c-Src kinase. Tyr 845 is positioned in the activation lip of the tyrosine kinase catalytic domain, and this residue is critical to catalytic function in other kinases. In this regard, cells expressing a Y845F variant of HER1 were greatly impaired in their ability to synthesize DNA in response to both EGF and serum.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1998
- Accession Number
- ADA356176
Entities
People
- Jacqueline Biscardi
Organizations
- University of Virginia