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Review
. 2022 Aug 31;10(9):2139.
doi: 10.3390/biomedicines10092139.

The Tyrosine Phosphatase SHP2: A New Target for Insulin Resistance?

Céline Saint-Laurent  1   2 , Laurène Mazeyrie  1 , Mylène Tajan  1 , Romain Paccoud  1 , Isabelle Castan-Laurell  1 , Philippe Valet  1 , Thomas Edouard  1   2 , Jean-Philippe Pradère  1 , Cédric Dray  1 , Armelle Yart  1
Affiliations
Review

The Tyrosine Phosphatase SHP2: A New Target for Insulin Resistance?

Céline Saint-Laurent et al. Biomedicines. .

Abstract

The SH2 containing protein tyrosine phosphatase 2(SHP2) plays essential roles in fundamental signaling pathways, conferring on it versatile physiological functions during development and in homeostasis maintenance, and leading to major pathological outcomes when dysregulated. Many studies have documented that SHP2 modulation disrupted glucose homeostasis, pointing out a relationship between its dysfunction and insulin resistance, and the therapeutic potential of its targeting. While studies from cellular or tissue-specific models concluded on both pros-and-cons effects of SHP2 on insulin resistance, recent data from integrated systems argued for an insulin resistance promoting role for SHP2, and therefore a therapeutic benefit of its inhibition. In this review, we will summarize the general knowledge of SHP2's molecular, cellular, and physiological functions, explaining the pathophysiological impact of its dysfunctions, then discuss its protective or promoting roles in insulin resistance as well as the potency and limitations of its pharmacological modulation.

Keywords: Noonan syndrome; SH2 containing protein tyrosine phosphatase 2; inflammation; insulin resistance; macrophage.

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Conflict of interest statement

A.Y., R.P., C.D., M.T., P.V. and J.-P.P. hold a patent for the use of shp2 inhibitors for the treatment of insulin resistance WO2020104635. The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
SH2 containing protein tyrosine phosphatase (SHP2) in insulin signaling: At the cellular level, SHP2 plays a negative role in insulin metabolic pathway by dephosphorylating phosphoinositide 3-kinase (PI3K)-binding sites (in yellow) and through RAS/Mitogen Activated Protein Kinase (MAPK)-dependent inhibitory phosphorylation (in red). This results in the downregulation of insulin-dependent glucose uptake and storage, and the increase of glucose production, notably in the liver, all contributing to hyperglycemia. In addition, SHP2 promotes a proinflammatory M1 state in macrophages, which triggers inflammation-dependent insulin resistance. On the other side, SHP2 has protective effects against insulin resistance by (i) promoting insulin biosynthesis in pancreas, (ii) regulating the development and function of adipose tissue, and (iii) stimulating central, leptin-dependent, energy expenditure. DAG: diacylglycerol, FFA: free fatty acid, InsR: insulin receptor. Created with BioRender.com accessed on 30 June 2022.
See this image and copyright information in PMC

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