Characterization of Heregulin-Stimulated Signal Transduction Pathways to the Nucleus.

The overexpression of members of the ErbB family of receptor tyrosine kinases has been implicated in different types of cancer, including breast cancer. Heregulin is the physiological ligand for ErbB3 and ErbB4, and upon ligand binding, these receptors can then dimerize with and activate ErbB2. In breast cancers where ErbB2 is overexpressed, the heregulin signal is constitutively active, even in the absence of ligand. Thus, understanding how heregulin signals are transduced in the cell and what cellular functions these signals are impacting upon should help us to identify molecular points for therapeutic intervention. Our work has identified the nuclear cap- binding complex CBC as a novel target for heregulin-stimulated signal transduction processes. The CBC plays a fundamental role in the regulation of gene expression at the level of RNA processing by influencing RNA splicing, export and 3-end processing events. Thus, it would appear that heregulin can impact upon these RNA metabolic events and we have demonstrated that the heregulin treatment of cells can induce RNA splicing. We now know that the heregulin signal is transmitted to the CBC via the Cdc42, FRAP and S6 kinase proteins. The heregulin treatment of cells also leads to a phosphorylation of the 80 kDa subunit of the CBC, suggesting a possible mechanism for CBC activation. We have shown that the S6 kinase can phosphorylate the CBC in vitro, and based on this information, we have constructed CBP80 mutants to identify the in vivo phosphorylation site, and determine whether this phosphorylation is essential for CBC activation.