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Chiang YA , Shao WJ , Xu XX , Chernoff J , Jin TR
P21-Activated Protein Kinase 1 (Pak1) Mediates the Cross Talk between Insulin and beta-Catenin on Proglucagon Gene Expression and Its Ablation Affects Glucose Homeostasis in Male C57BL/6 Mice
Endocrinology. 2013 Jan;154(1) :77-88
PMID: WOS:000312868500010   
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In gut endocrine L cells, the Wnt signaling pathway effector beta-catenin (beta-cat)/transcription factor 7-like 2 mediates the stimulatory effect of insulin on proglucagon (gcg) expression and glucagon-like peptide-1 (GLP-1) production. In several other cell lineages, insulin is able to stimulate p21-activated protein kinase 1 (Pak1). Here we determined the role of Pak1 in gcg expression and the effect of Pak1 deletion on glucose homeostasis. Insulin stimulated Pak1 activation through increasing its Thr423 phosphorylation in gut gcg-expressing cell lines, associated with increased gcg mRNA levels. This stimulation was attenuated by the Pak inhibitor 2,2'-dihydroxy-1,1'-dinaphthyldisulfide (IPA3) or dominant-negative Pak1. Both insulin and cAMP-promoting agents activated beta-cat Ser675 phosphorylation, which was attenuated by IPA3 or protein kinase A inhibition, respectively. Gut gcg levels were reduced in male Pak1(-/-) mice, associated with impaired glucose tolerance after an ip or oral glucose challenge. These mice had lower circulating active GLP-1 levels after a glucose challenge as well as reduced distal ileum GLP-1 content after insulin treatment. Finally, the Pak1(-/-) mice exhibited reduced brainstem gcg level and abolished beta-cat Ser675 phosphorylation in brain neurons after insulin treatment. We suggest that Pak1 mediates the cross talk between insulin and Wnt signaling pathways on gut and brain gcg expression, and its ablation impairs glucose homeostasis. (Endocrinology 154: 77-88, 2013)
ISI Document Delivery No.: 061SO Times Cited: 0 Cited Reference Count: 62 Chiang, Yuting Alex Shao, Weijuan Xu, Xiao Xue Chernoff, Jonathan Jin, Tianru Canadian Institutes of Health Research [MOP-89987]; Canadian Diabetes Association [OG-3-10-3040]; University Health Network-Banting and Best Diabetes Centre postdoctoral fellowship This work was supported by an Operating Grant MOP-89987 from the Canadian Institutes of Health Research (to T.J.) and an Operating Grant OG-3-10-3040 from the Canadian Diabetes Association (to T.J.). W. S. is supported by an University Health Network-Banting and Best Diabetes Centre postdoctoral fellowship. T.J. is the guarantor of the study. Endocrine soc Chevy chase