Activation by tyrosine phosphorylation as a prerequisite for protein kinase Cζ to mediate epidermal growth factor receptor signaling to ERK.
The atypical protein kinase Czeta (PKCzeta) was recently shown to mediate epidermal growth factor (EGF)-induced activation of extracellular signal-regulated kinase (ERK) in head and neck squamous carcinoma (HNSCC) cells. Here, it is shown that EGF may induce tyrosine phosphorylation of PKCzeta in several HNSCC cells, breast carcinoma cells, as well as mouse embryonic fibroblasts. In COS-7 cells overexpressing EGF receptor (EGFR) and PKCzeta as a tumor cell model, we show that PKCzeta tyrosine phosphorylation by EGF is induced by catalytic activation. Using a loss-of-function mutant of PKCzeta, we can show that the tyrosine residue 417 in PKCzeta plays an important role in both PKCzeta activation and the ability of PKCzeta to mediate activation of ERK. The importance of PKCzeta in EGF-induced ERK activation can also be shown in several HNSCC and breast carcinoma cell lines as well as in PKCzeta-deficient mouse embryonic fibroblasts. In addition, we present several lines of evidence suggesting the physical association of PKCzeta with EGFR and the importance of the EGFR tyrosine kinase c-Src and the Src-specific phosphorylation site pY845-EGFR in the tyrosine phosphorylation as well as catalytic activation of PKCzeta. This study characterizes PKCzeta as a novel mitogenic downstream mediator of EGFR and indicates PKCzeta as a therapeutic target in some carcinomas.
Valkova
Christina
C
Center of Molecular Biomedicine, Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Hans-Knöll-Strasse 2, D-07745 Jena, Germany.
Mertens
Carmen
C
Weisheit
Simona
S
Imhof
Diana
D
Liebmann
Claus
C
D000818:Animals; D019556:COS Cells; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D020134:Catalytic Domain / Q000235:genetics; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism*; D000099221:Protein Kinase C zeta
D066246:ErbB Receptors; D048052:Mitogen-Activated Protein Kinase 3; D011493:Protein Kinase C; D014443:Tyrosine; D000099221:Protein Kinase C zeta; C512478:EGFR protein, human