Characterization of Heregulin-Stimulated Signal Transduction Pathways to the Nucleus
Abstract
Heregulin is a glycoprotein ligand that interacts with the receptor tyrosine kinases, ErbB3 and ErbB4. This interaction induces a dimerization with and subsequent activation of the Neu/ErbB2 protein, which it turn initiates cellular signaling cascades. The signaling pathways that function as a consequence of Neu/ErbB2 activation are of great interest as the overexpression of Neu/ErbB2 is found in up to 40% of breast cancers and correlates with a poor prognosis for women with breast cancer. Mapping the molecular determinants of the heregulin/ErbB2 signaling pathway will be important in determining viable cellular targets for therapeutic intervention. To this end, we have identified the nuclear cap-binding complex (CBC) as a novel target for heregulin signaling. As the CBC plays an important role in the regulation of gene expression at the level of RNA processing, it is likely that heregulin can affect cell growth by altering the expression of genes important for mitogenesis. Indeed, we have shown heregulin to promote mRNA splicing, presumably through increasing the affinity of the CBC for capped RNAs. Additionally, we have determined some of the fundamental players in heregulin signaling to the CBC, including Cdc42, FRAP, and S6 kinase. Transforming alleles of Cdc42, like heregulin, can increase mRNA splicing, while a specific Cdc42 mutant which can no longer transform cells is no longer able to promote RNA splicing. Together these data identify a specific heregulin-Neu/ErbB2 pathway, and suggest a CBC-directed mechanism by which the activation of this pathway affects cell growth by altering post-transcriptional gene expression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2000
- Accession Number
- ADA389318
Entities
People
- Kristin Wilson
- Richard A. Cerione
Organizations
- Cornell University