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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 β-catenin (β-cat) in the nucleus and an increased association between β-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 β-cat phosphorylation at Ser675. Furthermore, PAK-1 silencing led to a complete blockade of insulin-stimulated β-cat binding to the c-Myc promoter and cellular growth. Finally, inhibition of MEK, a downstream target of PAK-1, blocked insulin-stimulated nuclear β-cat accumulation and c-Myc expression. Our observations suggest that PAK-1 serves as an important linker between insulin and Wnt signaling pathways.

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Acknowledgements

We thank Dr Jeffrey Field (University of Pennsylvania) for providing the dominant negative PAK-1 (K299R), constitutively active PAK-1 (T423E) and control plasmids. JS is a recipient of Banting and Best Diabetes Centre (BBDC) Novo Nordisk graduate studentship (2004–2008). This study was supported by an operating grant from Canadian Institutes of Health Research to TJ (MOP-89987) and a Translational Acceleration Research Grant from the Canadian Breast Cancer Research Alliance/CIHR (# 016512) to IGF.

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Correspondence to T Jin.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Sun, J., Khalid, S., Rozakis-Adcock, M. et al. P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine. Oncogene 28, 3132–3144 (2009). https://doi.org/10.1038/onc.2009.167

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