MassIVE MSV000084429

Partial Public PXD015733

Quantitative In Vivo Proteomics of Metformin Response in Liver Reveals AMPK-Dependent and -Independent Signaling Networks

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Description

Metformin is the front-line treatment for type 2 diabetes worldwide. It acts via effects on glucose and lipid metabolism in metabolic tissues, leading to enhanced insulin sensitivity. Despite significant effort, the molecular basis for metformin response remains poorly understood, with a limited number of specific biochemical pathways studied to date. To broaden our understanding of hepatic metformin response, we combine phospho-protein enrichment in tissue from genetically engineered mice with a quantitative proteomics platform to enable the discovery and quantification of basophilic kinase substrates in-vivo. We define proteins that binding to 14-3-3 are acutely regulated by metformin treatment and/or loss of the serine/threonine kinase, LKB1. Inducible binding of 250 proteins following metformin treatment is observed, 44% LKB1-dependent. Beyond AMPK, metformin activates Protein Kinase D and MAPKAPK2 in an LKB1-independent manner, revealing additional kinases that may mediate aspects of metformin response. Deeper analysis uncovered substrates of AMPK in endocytosis and calcium homeostasis. [doi:10.25345/C5D37X] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: metformin ; diabetes ; cancer ; aging ; AMPK ; LKB1 ; liver ; kinase ; 14-3-3 ; SILAM ; proteomics ; PKD ; MK2 ; STIM1 ; STIM2 ; calcium

Contact

Principal Investigators:
(in alphabetical order) 		John R. Yates III, The Scripps Research Institute, USA
Submitting User: salvador

Publications

Stein BD, Calzolari D, Hellberg K, Hu YS, He L, Hung CM, Toyama EQ, Ross DS, Lillemeier BF, Cantley LC, Yates JR, Shaw RJ.
Quantitative In Vivo Proteomics of Metformin Response in Liver Reveals AMPK-Dependent and -Independent Signaling Networks.
Cell Rep. 2019 Dec 3;29(10):3331-3348.e7.

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