Inhibition of C1-Ten PTPase activity reduces insulin resistance through IRS-1 and AMPK pathways

Abstract

Insulin resistance causes type 2 diabetes; therefore, increasing insulin sensitivity is a therapeutic approach against type 2 diabetes. Activating AMP-activated protein kinase (AMPK) is an effective approach for treating diabetes, and reduced insulin receptor substrate-1 (IRS-1) protein levels have been suggested as a molecular mechanism causing insulin resistance. Thus, dual targeting of AMPK and IRS-1 might provide an ideal way to treat diabetes. We found that 15,16-dihydrotanshinone I (DHTS), as a C1-Ten protein tyrosine phosphatase inhibitor, increased IRS-1 stability, improved glucose tolerance and reduced muscle atrophy. Identification of DHTS as a C1-Ten inhibitor revealed a new function of C1-Ten in AMPK inhibition, possibly through regulation of IRS-1. These findings suggest that C1-Ten inhibition by DHTS could provide a novel therapeutic strategy for insulin resistance-associated metabolic syndrome through dual targeting of IRS-1 and AMPK.

Hepatoprotective Effect of Loquat Leaf Flavonoids in PM2.5-Induced Non-Alcoholic Fatty Liver Disease via Regulation of IRs-1/Akt and CYP2E1/JNK Pathways

“…Insulin receptor substrate-1 (IRs-1) as a protein phosphorylated by insulin receptor tyrosine kinase, is responsible for the transduction of insulin signaling. Impaired responsiveness to insulin leads to IR, which typically occurs at the level of IRs-1, has been observed in metabolic disorders, including type 2 diabetes and NAFLD [ 33 , 34 ]. Restoration of IRs-1 is essential for insulin signaling, which might be beneficial for attenuating NAFLD [ 35 ].…”

Cellular phosphatase activity of C1-Ten/Tensin2 is controlled by Phosphatidylinositol-3,4,5-triphosphate binding through the C1-Ten/Tensin2 SH2 domain

“…The SH2 domain (amino acids 1120–1253) of C1-Ten was inserted between the Xho I and Eco RI restriction sites of pRSET-B vector (Invitrogen, Carlsbad, CA, USA) with a His 6 tag at the N-terminus and an EGFP epitope at the C-terminus for SPR analysis. Full-length C1-Ten was sub-cloned into the Eco RI and Xba I restriction sites of the p3XFlag-CMV10 vector (Sigma Aldrich) [14] for stable expression in HEK293 cells. Point mutations of C1-Ten were generated with a QuickChange site-directed mutagenesis kit (Stratagene, La Jolla, CA, USA).…”

“…A PTP assay was performed and its activity was calculated as previously described [13, 14]. Briefly, three 10-cm dishes containing HEK293 cells were transfected with 3 μg Flag C1-Ten plasmids.…”

“…We identified the metabolic role of C1-Ten as an active PTP of insulin signaling components, which regulate the phosphoinositide 3-kinase (PI3K) binding site, and contributes to pathological conditions such as diabetes [12, 13]. In addition, it has been suggested that C1-Ten may be an interesting therapeutic target in diabetes, because its expression appears upregulated under such conditions and may lead to insulin resistance [14]. C1-Ten is a relevant PTP in insulin signaling that directly interacts with IRS-1, without affecting insulin receptor tyrosine phosphorylation [13].…”

Hepatoprotective Effect of Seed Coat of<i>Euryale ferox</i> Extract in Non-alcoholic Fatty Liver Disease Induced by High-fat Diet in Mice by Increasing IRs-1 and Inhibiting CYP2E1

“…As a protein phosphorylated by insulin receptor tyrosine kinase, insulin receptor substrate-1 IRs-1 is responsible for the transduction of insulin signaling. Impaired insulin signaling leading to IR, which typically occurs at the level of IRs-1, has been observed in metabolic disorders including NAFLD 12,13 . Restoration of IRs-1 is essential for proper insulin signaling, which might be beneficial for attenuating NAFLD 14 .…”