PKCε acts as negative allosteric modulator of EGF receptor signalling

Protein kinase C epsilon (PKC epsilon) is a transforming oncogene and plays a pivotal role in numerous cellular processes including proliferation, invasion and differentiation. Recently, we described a function of PKC epsilon as a scaffold protein linking PLC gamma 1 to the EGFR module. Here, in the head and neck squamous carcinoma cell line (HNSCC) FaDu we demonstrate that over-expressed PKC epsilon may be associated with the EGFR. This is linked with the consecutive inhibition of the recruitment of PLC gamma 1 to the EGFR, of the catalytical activation of PLC gamma 1 by EGF, and of the PLC gamma 1-mediated effect of EGF on cell proliferation. These effects are independent of the catalytical as well as the scaffold activity of PKC epsilon but are a function of the cellular expression level of PKC epsilon. In contrast to FaDu cells where the PLC gamma 1 pathway was selectively affected, in three other HNSCC cell lines investigated over-expression of PKC epsilon resulted in association with EGFR and, subsequently, in either partial (ERK and Akt or PLC gamma 1 and Akt) or complete (ERK, PLC gamma 1 and Akt) inhibition of the main EGFR signalling pathways. Together, our data suggest that in particular carcinoma cells highly expressed PKC epsilon may act as negative allosteric modulator of EGFR signalling. This novel function of PKC epsilon provides also the first indication that the EGFR may be a target for allosteric modulation by accessory proteins. (C) 2010 Elsevier Inc. All rights reserved.