Knockout of PKC alpha enhances insulin signaling through PI3K.
Insulin stimulates glucose transport and certain other metabolic processes by activating atypical PKC isoforms (lambda, zeta, iota) and protein kinase B (PKB) through increases in D3-polyphosphoinositides derived from the action of PI3K. The role of diacylglycerol-sensitive PKC isoforms is less clear as they have been suggested to be both activated by insulin and yet inhibit insulin signaling to PI3K. Presently, we found that insulin signaling to insulin receptor substrate 1-dependent PI3K, PKB, and PKC lambda, and downstream processes, glucose transport and activation of ERK, were enhanced in skeletal muscles and adipocytes of mice in which the ubiquitous conventional diacylglycerol-sensitive PKC isoform, PKC alpha, was knocked out by homologous recombination. On the other hand, insulin provoked wortmannin-insensitive increases in immunoprecipitable PKC alpha activity in adipocytes and skeletal muscles of wild-type mice and rats. We conclude that 1) PKC alpha is not required for insulin-stimulated glucose transport, and 2) PKC alpha is activated by insulin at least partly independently of PI3K, and largely serves as a physiological feedback inhibitor of insulin signaling to the insulin receptor substrate 1/PI3K/PKB/PKC lambda/zeta/iota complex and dependent metabolic processes.
Leitges
Michael
M
Max-Planck Institute for Experimental Endocrinology, 30625 Hannover, Germany.
Plomann
Markus
M
Standaert
Mary L
ML
Bandyopadhyay
Gautam
G
Sajan
Mini P
MP
Kanoh
Yoshinori
Y
Farese
Robert V
RV
Letiges
Michael
M
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D001786:Blood Glucose / Q000378:metabolism; D004789:Enzyme Activation; D007328:Insulin / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051571:Protein Kinase C-alpha; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000099293:Protein Kinase C-lambda
D001786:Blood Glucose; D007328:Insulin; D007527:Isoenzymes; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000099293:Protein Kinase C-lambda; C496630:Prkca protein, mouse