Phosphoproteomics reveals rewiring of the insulin signaling network and multi-nodal defects in insulin resistance.


Type
Article
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Authors
Fazakerley, Daniel J  ORCID logo  https://orcid.org/0000-0001-8241-2903
van Gerwen, Julian 
Cooke, Kristen C 
Duan, Xiaowen 
Needham, Elise J 
Abstract

The failure of metabolic tissues to appropriately respond to insulin ("insulin resistance") is an early marker in the pathogenesis of type 2 diabetes. Protein phosphorylation is central to the adipocyte insulin response, but how adipocyte signaling networks are dysregulated upon insulin resistance is unknown. Here we employ phosphoproteomics to delineate insulin signal transduction in adipocyte cells and adipose tissue. Across a range of insults causing insulin resistance, we observe a marked rewiring of the insulin signaling network. This includes both attenuated insulin-responsive phosphorylation, and the emergence of phosphorylation uniquely insulin-regulated in insulin resistance. Identifying dysregulated phosphosites common to multiple insults reveals subnetworks containing non-canonical regulators of insulin action, such as MARK2/3, and causal drivers of insulin resistance. The presence of several bona fide GSK3 substrates among these phosphosites led us to establish a pipeline for identifying context-specific kinase substrates, revealing widespread dysregulation of GSK3 signaling. Pharmacological inhibition of GSK3 partially reverses insulin resistance in cells and tissue explants. These data highlight that insulin resistance is a multi-nodal signaling defect that includes dysregulated MARK2/3 and GSK3 activity.

Description
Keywords
Humans, Diabetes Mellitus, Type 2, Glycogen Synthase Kinase 3, Insulin, Insulin Resistance, Phosphorylation, Signal Transduction, Proteome
Journal Title
Nat Commun
Conference Name
Journal ISSN
2041-1723
2041-1723
Volume Title
Publisher
Nature Research
Sponsorship
Medical Research Council (MR/S007091/1)
Wellcome Trust (204845/Z/16/Z)
Wellcome Trust (208363/Z/17/Z)