Abstract
The protein kinase C (PKC) family of serine/threonine kinases participate in embryonic stem cell (ESC) proliferation/self-renewal. A few stimuli that induce ESC proliferation activate several PKC isoenzymes including δPKC, however, the role of this isoenzyme under basal conditions that maintain undifferentiated ESCs remains to be determined. Herewith, we aimed to characterize signaling events that occur in undifferentiated ESCs upon δPKC activation. Using phosphoproteomics and a δPKC specific activator peptide, ψδRACK, it was seen that the majority of proteins whose phosphorylation increased upon δPKC activation participate in cell proliferation. Network analysis of these proteins directly connected δPKC to Raf1 and 14-3-3. Experimental validation studies showed that activation of δPKC increased its binding to 14-3-3, transiently activated ERK1/2 and increased ESC proliferation. Independently inhibiting MEK or PI3 kinase both led to a decrease in proliferation of approximately 50%, but δPKC activation only recovered the effect of PI3 kinase inhibition suggesting that ERK1/2 activation via δPKC is probably a parallel pathway to PI3 kinase and that both pathways are necessary for undifferentiated ESC proliferation. The use of emb...Continue Reading
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