Behera, S. and Kapadia, B. and Vasundhara, K. and Neeraja, A.Y.P. and Vachana, M. and Kumar, S.T. and Prakash Babu, P. and Seshadri, S. and Shivarudraiah, P. and Hiriyan, J. and Narmadha Reddy, Gangula and Subba Reddy, Maddika and Misra, P. and Parsa, K.V.L. (2018) ERK1/2 activated PHLPP1 induces skeletal muscle ER stress through the inhibition of a novel substrate AMPK. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1864 (5A). pp. 1702-1716. ISSN 0925-4439

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Abstract

Nutritional abundance associated with chronic inflammation and dyslipidemia impairs the functioning of endoplasmic reticulum (ER) thereby hampering cellular responses to insulin. PHLPP1 was identified as a phosphatase which inactivates Akt, the master regulator of insulin mediated glucose homeostasis. Given the suggestive role of PHLPP1 phosphatase in terminating insulin signalling pathways, deeper insights into its functional role in inducing insulin resistance are warranted. Here, we show that PHLPP1 expression is enhanced in skeletal muscle of insulin resistant rodents which also displayed ER stress, an important mediator of insulin resistance. Using cultured cells and PHLPP1 knockdown mice, we demonstrate that PHLPP1 facilitates the development of ER stress. Importantly, shRNA mediated ablation of PHLPP1 significantly improved glucose clearance from systemic circulation with enhanced expression of glucose transporter 4 (GLUT-4) in skeletal muscle. Mechanistically, we show that endogenous PHLPP1 but not PP2Cα interacts with and directly dephosphorylates AMPK Thr172 in myoblasts without influencing its upstream kinase, LKB1. While the association between endogenous PHLPP1 and AMPK was enhanced in ER stressed cultured cells and soleus muscle of high fat diet fed mice, the basal interaction between PP2Ac and AMPK was minimally altered. Further, we show that PHLPP1α is phosphorylated by ERK1/2 at Ser932 under ER stress which is required for its ability to interact with and dephosphorylate AMPK and thereby induce ER stress. Taken together, our data position PHLPP1 as a key regulator of ER stress.

Item Type:	Article
Depositing User:	Users 2 not found.
Date Deposited:	01 Mar 2018 06:28
Last Modified:	26 Apr 2018 19:06
URI:	http://cdfd.sciencecentral.in/id/eprint/829

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