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Structural Studies of a New Nuclear Target for EGF Receptor Tyrosine Kinases
Annual summary rept. 15 Jul 2000-14 Jul 2001
CORNELL UNIV ITHACA NY
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This project involves structural studies of a nuclear target for the EGF receptor, and the elated NeuErbB2 tyrosine kinase, named the CBC for RNA-capped binding protein complex. The CBC consists of two subunits, CBP20 Mr 18 Kda and CBPBO Mr 90 Kda, and undergoes a growth factor EGF, heregulin-dependent binding of RNAs transcribed by the RNA polymerase II at a 5 cap structure that consists of a guanosine residue methylated at the N7 position. This represents a first key step in the cap-dependent splicing of precursor messenger RNA mRNA and in the mucleocytoplasmic transport of U snRNAs which are necessary for the formation of the spliceosome complexes. While, EGF stimulates CBC activity, it is most strongly stimulated by heregulin, an activator of the NeuErbB2 tyrosine kinase, and appears to be constitutive in breast cancer where NeuErbB2 expression is high. Thus, we believe that the CBC represents an exciting nuclear target for receptor tyrosine kinases, linking growth factor-dependent gene expression to RNA processing. We have solved the atomic structure of the CBC in complex with m7GpppG at 2.2 A. The atomic structure of this triple complex represents the second eukaryotic cap binding structure solved to date and reveals interesting aspects of capped RNA binding and regulation.
APPROVED FOR PUBLIC RELEASE