Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Tortora, G. et al.

The RIalpha subunit of protein kinase A (PKA) binds to Grb2 and allows PKA interaction with the activated EGF-receptor.

Functional interactions between protein kinase A (PKA) and epidermal growth factor receptor (EGF-R) signalling pathways have been suggested. Unlike the type II isoform of PKA (PKAII), the type I (PKAI) and/or its regulatory subunit RIalpha are generally overexpressed in cancer cells and are induced following transforming growth factor alpha (TGF alpha)/EGF-R-dependent transformation. Downregulation of RIalpha/PKAI inhibits TGF alpha expression and EGF-R-dependent signalling. We have previously shown that addition of EGF to quiescent human normal epithelial MCF-10A cells determines PKAI expression and cell membrane translocation before cells enter S phase, while PKAI inhibition prevents S phase entry. Constitutive overexpression of PKAI confers the ability to grow in serum free medium, bypassing EGF requirement. Here we demonstrate a direct interaction of PKAI, but not of PKAII, with the activated EGF-R, that occurs within 5 min following EGF treatment of MCF-10A cells. Moreover, induction of mitogen-activated protein kinase ( MAPK) activity following EGF-R activation is mimicked by PKAI overexpression and inhibited by downregulators of PKAI. Finally, the PKAI-EGF-R association occurs through the binding of RIalpha to the SH3 domain(s) of Grb2 adaptor protein, thus allowing the recruitment of the PKAI holoenzyme to the activated EGF-R. This is the first demonstration of a direct interaction of PKAI with the activated EGF-R macromolecular signalling complex.[1]

References

The RIalpha subunit of protein kinase A (PKA) binds to Grb2 and allows PKA interaction with the activated EGF-receptor. Tortora, G., Damiano, V., Bianco, C., Baldassarre, G., Bianco, A.R., Lanfrancone, L., Pelicci, P.G., Ciardiello, F. Oncogene (1997) [Pubmed]

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