Regulation of ERBB Receptor Tyrosine Kinase Activities in Breast Cancer by the KEK Proteins
Abstract
We have found that the Drosophila transmembrane molecule kekkon 1 (keki) acts in a negative feed back loop to modulate the activity of the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase. keki is expressed in response to activation of the Gurken/EGFR signaling pathway during oogenesis. While loss of keki activity is associated with a phenotype reminiscent of increased Grk/EGFR signaling, ectopic overexpression of keki rnmics the complete loss of EGFR activity. We found that the extracellular domain of Keki physically associates with the EGFR providing the basis for this inhibitory mechanism. Interestingly, we found that Keki is also a potent inhibitor of the EGFR in mammalian cells. First, Kek1 binds the ECFR and related proteins ErbB2, ErbB3 and ErbB4. Keki interferes with EGF mediated receptor tyrosine phosphorylation and activation of the downstream signaling molecules P13-kinase and Erk/MAP kinases. Kek1 can also inhibit transformation in mouse mammary tumor cells with deregulated expression of receptors and ligands of the ErbB family.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 1999
- Accession Number
- ADA385418
Entities
People
- Norbert Perrimon
Organizations
- Harvard University