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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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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DOI: https://doi.org/10.1038/onc.2009.167
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