Protein kinase C (PKC) betaII induces cell invasion through a Ras/Mek-, PKC iota/Rac 1-dependent signaling pathway.
Protein kinase C betaII (PKCbetaII) promotes colon carcinogenesis. Expression of PKCbetaII in the colon of transgenic mice induces hyperproliferation and increased susceptibility to colon cancer. To determine molecular mechanisms by which PKCbetaII promotes colon cancer, we established rat intestinal epithelial (RIE) cells stably expressing PKCbetaII. Here we show that RIE/PKCbetaII cells acquire an invasive phenotype that is blocked by the PKCbeta inhibitor LY379196. Invasion is not observed in RIE cells expressing a kinase-deficient PKCbetaII, indicating that PKCbetaII activity is required for the invasive phenotype. PKCbetaII induces activation of K-Ras and the Ras effector, Rac1, in RIE/PKCbetaII cells. PKCbetaII-mediated invasion is blocked by the Mek inhibitor, U0126, and by expression of either dominant negative Rac1 or kinase-deficient atypical PKCiota. Expression of constitutively active Rac1 induces Mek activation and invasion in RIE cells, indicating that Rac1 is the critical downstream effector of PKCbetaII-mediated invasion. Taken together, our results define a novel PKCbetaII --> Ras --> PKCiota /Rac1 --> Mek signaling pathway that induces invasion in intestinal epithelial cells. This pathway provides a plausible mechanism by which PKCbetaII promotes colon carcinogenesis.
Zhang
Jie
J
Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224, USA.
Anastasiadis
Panos Z
PZ
Liu
Yan
Y
Thompson
E Aubrey
EA
Fields
Alan P
AP
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002070:Butadienes / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008565:Membrane Proteins; D008698:Mesylates / Q000494:pharmacology; D008954:Models, Biological; D009154:Mutation; D009361:Neoplasm Invasiveness; D009570:Nitriles / Q000494:pharmacology; D010641:Phenotype; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism* / Q000502:physiology*; D064546:Protein Kinase C beta; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*; D000099293:Protein Kinase C-lambda
D051017:Apoptosis Regulatory Proteins; D002070:Butadienes; D002352:Carrier Proteins; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors; D019204:GTP-Binding Proteins; D005982:Glutathione Transferase; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D008698:Mesylates; D009570:Nitriles; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D017346:Protein Serine-Threonine Kinases; D011758:Pyrroles; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins; D000099293:Protein Kinase C-lambda; C434605:5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate; C100494:RTKN protein, human; C498396:Rtkn protein, rat; C113580:U 0126; C496540:PTGS2 protein, human; C482576:MAP3K1 protein, human