Role of PTPase LAR in EGF Receptor in the Mammary Gland
Abstract
The epidermal growth factor receptor (EGFR) is an important mediator of breast cancer tumorigenesis and metastasis. While much is known about EGFR signal transduction related to its tyrosine kinase activity, less is known about the protein tyrosine phosphatases (PTPs) which must be present to modulate the cellular effects of the EGFR by dephosphorylating the receptor and its substrates. Evidence derived from several approaches suggests that the transmembrane PTP LAR may be involved in EGFR signaling in mammary gland development and tumorigenesis. The hypothesis to be tested in this proposal is that LAR plays an important role in EGFR-dependent mammary gland development and tumorigenesis through negative modulation of EGFR signal transduction. In year 2, we demonstrated that LAR expression is regulated by cell density, with concentrations increasing markedly as cell density increases. Functional E-cadherin complexes are necessary for this effect. Additionally, we showed that cell contact inhibits EGF- dependent proliferation in MCF10A mammary tumor cells and is mediated at the level of Akt activation. E-cadherin complexes are presumed to be the mediators of this cell contact inhibition. In year 3, we have shown that cell contact inhibition of Akt blocks the cell cycle. The central role of Akt regulation in this pathway is confirmed by recapitulating the effect with an adenovirus-mediated expression of a dominant negative Akt. Finally, transgenic expression of LAR in mammary epithelium under the MMTV promoter did not generate abnormal rates of spontaneous tumors. Taken together, these data indicate that the critical regulation of EGF signaling is not at the receptor via LAR but downstream at Akt.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2004
- Accession Number
- ADA427953
Entities
People
- Robert A. Mooney
Organizations
- University of Rochester