P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine.
Hyperinsulinemia and type II diabetes are associated with an increased risk of developing colorectal tumors. We found previously that in intestinal cells, insulin or insulin-like growth factor-1 stimulates c-Myc and cyclin D1 protein expression through both Akt-dependent and Akt-independent mechanisms. The effect of Akt is attributed to the stimulation of c-Myc translation by mammalian target of rapamycin. However, Akt-independent stimulation was, associated with an increase in beta-catenin (beta-cat) in the nucleus and an increased association between beta-cat and T-cell factor binding sites on the c-Myc promoter, detected by chromatin immunoprecipitation. In this study, we show that insulin stimulated the phosphorylation/activation of p-21-activated protein kinase-1 (PAK-1) in an Akt-independent manner in vitro and in an in vivo hyperinsulinemic mouse model. Significantly, shRNA (small hairpin RNA)-mediated PAK-1 knockdown attenuated both basal and insulin-stimulated c-Myc and cyclin D1 expression, associated with a marked reduction in extracellular signal-regulated kinase activation and beta-cat phosphorylation at Ser675. Furthermore, PAK-1 silencing led to a complete blockade of insulin-stimulated beta-cat binding to the c-Myc promoter and cellular growth. Finally, inhibition of MEK, a downstream target of PAK-1, blocked insulin-stimulated nuclear beta-cat accumulation and c-Myc expression. Our observations suggest that PAK-1 serves as an important linker between insulin and Wnt signaling pathways.
Sun
J
J
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Khalid
S
S
Rozakis-Adcock
M
M
Fantus
I G
IG
Jin
T
T
D000818:Animals; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
D007328:Insulin; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases