PKCε acts as negative allosteric modulator of EGF receptor signalling.
Protein kinase C ε (PKCε) is a transforming oncogene and plays a pivotal role in numerous cellular processes including proliferation, invasion and differentiation. Recently, we described a function of PKCε as a scaffold protein linking PLCγ1 to the EGFR module. Here, in the head and neck squamous carcinoma cell line (HNSCC) FaDu we demonstrate that over-expressed PKCε may be associated with the EGFR. This is linked with the consecutive inhibition of the recruitment of PLCγ1 to the EGFR, of the catalytical activation of PLCγ1 by EGF, and of the PLCγ1-mediated effect of EGF on cell proliferation. These effects are independent of the catalytical as well as the scaffold activity of PKCε but are a function of the cellular expression level of PKCε. In contrast to FaDu cells where the PLCγ1 pathway was selectively affected, in three other HNSCC cell lines investigated over-expression of PKCε resulted in association with EGFR and, subsequently, in either partial (ERK and Akt or PLCγ1 and Akt) or complete (ERK, PLCγ1 and Akt) inhibition of the main EGFR signalling pathways. Together, our data suggest that in particular carcinoma cells highly expressed PKCε may act as negative allosteric modulator of EGFR signalling. This novel function of PKCε provides also the first indication that the EGFR may be a target for allosteric modulation by accessory proteins.
Center of Molecular Biomedicine, Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Jena, Germany.
Simona
S
Weisheit
Claudia
C
Schäfer
Carmen
C
Mertens
Alexander
A
Berndt
Claus
C
Liebmann
D000494:Allosteric Regulation; D000818:Animals; D019556:COS Cells; D002465:Cell Movement; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D051379:Mice; D051966:Phospholipase C gamma / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D066246:ErbB Receptors; D051744:Protein Kinase C-epsilon; D051966:Phospholipase C gamma