Characterization of Heregulin-Stimulated Signal Transduction Pathways to the Nucleus.
Annual rept. 25 Aug 97-24 Aug 98
CORNELL UNIV ITHACA NY
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The epidermal growth factor EGF receptor subfamily of receptor tyrosine kinases, including NeuErbB2, ErbB3 and ErbB4, has been implicated in the development of many breast cancers. Heregulin HRG has been identified as the ligand for these receptors, and this ligand-receptor interaction is the first step in a signaling pathway which is presumably overactive in tumors where the above named ErbB receptors are overexpressed. Our goal was to attempt to uncover the downstream effects of HRG in the cell. In particular, we proposed to investigate an 18 kDa nuclear protein, p18, which responded to HRG signals with a dramatically enhanced ability to bind GTP. In this report, we have identified p18 as CBP2O, the 20 kDa subunit of the nuclear cap-binding complex CBC. The CBC binds to capped RNAs, and in so doing, has been shown to facilitate cap-dependent pre-mRNA splicing and export. We have demonstrated that the CBC binds to capped RNAs in response to stimuli, and that cap-dependent RNA splicing is enhanced in cells treated with HRG. Additionally, we now find that multiple signaling pathways may be involved in the activation of the CBC to bind to capped RNAs.
- Anatomy and Physiology
- Medicine and Medical Research