title: P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine.
abstract: 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.
authors: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: J
authors: J
authors: Sun
authors: S
authors: S
authors: Khalid
authors: M
authors: M
authors: Rozakis-Adcock
authors: I G
authors: IG
authors: Fantus
authors: T
authors: T
authors: Jin
mesh_terms: 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*
chemical_list: 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