Protein tyrosine phosphatases (PTPs) in diabetes: causes and therapeutic opportunities

Nepetin Acts as a Multi‐Targeting Inhibitor of Protein Tyrosine Phosphatases Relevant to Insulin Resistance

“…Nepetin Inhibits the Catalytic Activity of PTPN1, PTPN2, and PTPN11 in Vitro Since certain PTPs, such as PTPN1, PTPN2, PTPN9, PTPN11, PTPRS, PTPRA, and DUSP9 related to insulin resistance, are promising drug targets for treating type 2 diabetes, inhibitors of PTPs involved in type 2 diabetes have been reported to have antidiabetic properties. [2] As PTPN1, PTPN2, and PTPN11 have been reported to be negative regulators of insulin signaling, [2,4,18] the identification of these PTPs inhibitors could be a useful strategy for developing therapeutic candidates for the treatment of type 2 diabetes. In this study, PTPN1, PTPN2, and PTPN11 were overexpressed in E. coli and purified using a cobalt affinity resin (Figure 1a-c).…”

“…Since some PTPs, such as PTPN1, PTPN2, PTPN9, PTPN11, PTPRS, PTPRA, and DUSP9, are related to insulin resistance and thus are potential drug targets for the treatment of type 2 diabetes, [2] development of inhibitors against these PTPs is a useful strategy for treating type 2 diabetes. Here, we show for the first time that nepetin inhibits the catalytic activity of PTPN1, PTPN2, and PTPN11, indicating that nepetin targets these PTPs.…”

“…Some natural products have been shown to stimulate insulin signaling through inhibition of PTPs, and corosolic acid, a triterpenoid compound found in many herbal medicines, improves glucose uptake by inhibiting the enzymatic activity of several PTPs such as PTPN1, PTPN2, PTPN6, and PTPN11. [2,20] To determine the appropriate concentration of nepetin to be applied to 3T3-L1 adipocytes, cell viability was measured using an EZ-Cytox assay kit. We observed that incubation of differentiated 3T3-L1 adipocytes with 1, 10, or 20 μM nepetin for 48 h did not affect cell viability, indicating that these concentrations were suitable for cell treatment (Figure 2a).…”

“…Protein tyrosine phosphorylation plays a central role in cellular functions such as cell growth, differentiation, migration, survival, and apoptosis and is modulated by protein tyrosine kinases and protein tyrosine phosphatases (PTPs). [1,2] PTPs, also known as essential modulators of signal transduction pathways, contribute to a variety of human diseases, including cancer, diabetes, obesity, autoimmune disorders, and neurological diseases, indicating that PTPs are next-generation drug targets. [3] Some PTPs, such as PTPN1, PTPN2, PTPN9, PTPN11, PTPRS, and DUSP9, induce insulin resistance and contribute to metabolic disorders, suggesting that PTPs could be attractive targets to treat type 2 diabetes.…”

“…[3] Some PTPs, such as PTPN1, PTPN2, PTPN9, PTPN11, PTPRS, and DUSP9, induce insulin resistance and contribute to metabolic disorders, suggesting that PTPs could be attractive targets to treat type 2 diabetes. [2,4] Adenosine monophosphate-activated protein kinase (AMPK), a cellular energy sensor, controls glucose and lipid metabolism, and its activation promotes glucose uptake by inducing glucose trans-porter type 4 translocation to the plasma membrane, indicating that AMPK is an attractive target for the treatment of type 2 diabetes. [5,6] PTP non-receptor type 1 (PTPN1, also called PTP1B) acts as a negative regulator of insulin signaling pathways by dephosphorylating the insulin receptor, suggesting that the inhibition of PTPN1 may be a promising approach for the treatment of type 2 diabetes.…”