Different protein kinase C isoforms determine growth factor specificity in neuronal cells.
Although mitogenic and differentiating factors often activate a number of common signaling pathways, the mechanisms leading to their distinct cellular outcomes have not been elucidated. In a previous report, we demonstrated that mitogen-activated protein (MAP) kinase (ERK) activation by the neurogenic agents fibroblast growth factor (FGF) and nerve growth factor is dependent on protein kinase Cdelta (PKCdelta), whereas MAP kinase activation in response to the mitogen epidermal growth factor (EGF) is independent of PKCdelta in rat hippocampal (H19-7) and pheochromocytoma (PC12) cells. We now show that EGF activates MAP kinase through a PKCzeta-dependent pathway involving phosphatidylinositol 3-kinase and PDK1 in H19-7 cells. PKCzeta, like PKCdelta, acts upstream of MEK, and PKCzeta can potentiate Raf-1 activation by EGF. Inhibition of PKCzeta also blocks EGF-induced DNA synthesis as monitored by bromodeoxyuridine incorporation in H19-7 cells. Finally, in embryonic rat brain hippocampal cell cultures, inhibitors of PKCzeta or PKCdelta suppress MAP kinase activation by EGF or FGF, respectively, indicating that these factors activate distinct signaling pathways in primary as well as immortalized neural cells. Taken together, these results implicate different PKC isoforms as determinants of growth factor signaling specificity within the same cell. Furthermore, these data provide a mechanism whereby different growth factors can differentially activate a common signaling intermediate and thereby generate biological diversity.
Corbit
K C
KC
Neurobiology, Pharmacology and Physiology Department and Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA.
Soh
J W
JW
Yoshida
K
K
Eves
E M
EM
Weinstein
I B
IB
Rosner
M R
MR
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000196:embryology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016716:PC12 Cells / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D064413:3-Phosphoinositide-Dependent Protein Kinases; D004815:Epidermal Growth Factor; D007527:Isoenzymes; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016376:Oligonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D000074121:Protein Kinase C-theta; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; C497260:Prkcd protein, rat; C578579:Pdpk1 protein, rat; C489591:Prkcq protein, rat