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 (kek1) acts in a negative feed back loop to modulate the activity of the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase. kek1 is expressed in response to activation of the Gurken/EGFR signaling pathway during oogenesis. While loss of kek1 activity is associated with a phenotype reminiscent of increased Grk/EGFR signaling, ectopic overexpression of kek1 mimics the complete loss of EGFR activity. We found that the extracellular domain of Kek1 physically associates with the EGFR providing the basis for this inhibitory mechanism. Interestingly, we found that Kek1 is also a potent inhibitor of the EGFR in mammalian cells. First, Kek1 binds the EGFR and related proteins ErbB2, ErbB3 and ErbB4. Kek1 interferes with EGF mediated receptor tyrosine phosphorylation and activation of the downstream signaling molecules PI3-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
- Oct 01, 2000
- Accession Number
- ADA388532
Entities
People
- Norbert M. Perrimon
Organizations
- Harvard University