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The Role of Protein Tyrosine Phosphatase (PTP)-1B in Cardiovascular Disease and Its Interplay with Insulin Resistance.

ABSTRACT: Endothelial dysfunction is a key feature of cardiovascular disorders associated with obesity and diabetes. Several studies identified protein tyrosine phosphatase (PTP)-1B, a member of the PTP superfamily, as a major negative regulator for insulin receptor signaling and a novel molecular player in endothelial dysfunction and cardiovascular disease. Unlike other anti-diabetic approaches, genetic deletion or pharmacological inhibition of PTP1B was found to improve glucose homeostasis and insulin signaling without causing lipid buildup in the liver, which represents an advantage over existing therapies. Furthermore, PTP1B was reported to contribute to cardiovascular disturbances, at various molecular levels, which places this enzyme as a unique single therapeutic target for both diabetes and cardiovascular disorders. Synthesizing selective small molecule inhibitors for PTP1B is faced with multiple challenges linked to its similarity of sequence with other PTPs; however, overcoming these challenges would pave the way for novel approaches to treat diabetes and its concurrent cardiovascular complications. In this review article, we summarized the major roles of PTP1B in cardiovascular disease with special emphasis on endothelial dysfunction and its interplay with insulin resistance. Furthermore, we discussed some of the major challenges hindering the synthesis of selective inhibitors for PTP1B.

SUBMITTER: Abdelsalam SS

PROVIDER: S-EPMC6680919 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The Role of Protein Tyrosine Phosphatase (PTP)-1B in Cardiovascular Disease and Its Interplay with Insulin Resistance.

Abdelsalam Shahenda S SS Korashy Hesham M HM Zeidan Asad A Agouni Abdelali A

Biomolecules 20190717 7

Endothelial dysfunction is a key feature of cardiovascular disorders associated with obesity and diabetes. Several studies identified protein tyrosine phosphatase (PTP)-1B, a member of the PTP superfamily, as a major negative regulator for insulin receptor signaling and a novel molecular player in endothelial dysfunction and cardiovascular disease. Unlike other anti-diabetic approaches, genetic deletion or pharmacological inhibition of PTP1B was found to improve glucose homeostasis and insulin s ...[more]

PMID: 31319588

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Project description:The tyrosine kinase Fyn has two regulatory tyrosine residues that when phosphorylated either activate (Tyr(420)) or inhibit (Tyr(531)) Fyn activity. Within the central nervous system, two protein tyrosine phosphatases (PTPs) target these regulatory tyrosines in Fyn. PTP? dephosphorylates Tyr(531) and activates Fyn, while STEP (STriatal-Enriched protein tyrosine Phosphatase) dephosphorylates Tyr(420) and inactivates Fyn. Thus, PTP? and STEP have opposing functions in the regulation of Fyn; however, whether there is cross talk between these two PTPs remains unclear. Here, we used molecular techniques in primary neuronal cultures and in vivo to demonstrate that STEP negatively regulates PTP? by directly dephosphorylating PTP? at its regulatory Tyr(789). Dephosphorylation of Tyr(789) prevents the translocation of PTP? to synaptic membranes, blocking its ability to interact with and activate Fyn. Genetic or pharmacologic reduction in STEP61 activity increased the phosphorylation of PTP? at Tyr(789), as well as increased translocation of PTP? to synaptic membranes. Activation of PTP? and Fyn and trafficking of GluN2B to synaptic membranes are necessary for ethanol (EtOH) intake behaviors in rodents. We tested the functional significance of STEP61 in this signaling pathway by EtOH administration to primary cultures as well as in vivo, and demonstrated that the inactivation of STEP61 by EtOH leads to the activation of PTP?, its translocation to synaptic membranes, and the activation of Fyn. These findings indicate a novel mechanism by which STEP61 regulates PTP? and suggest that STEP and PTP? coordinate the regulation of Fyn. STEP61 , PTP?, Fyn, and NMDA receptor (NMDAR) have been implicated in ethanol intake behaviors in the dorsomedial striatum (DMS) in rodents. Here, we report that PTP? is a novel substrate for STEP61. Upon ethanol exposure, STEP61 is phosphorylated and inactivated by protein kinase A (PKA) signaling in the DMS. As a result of STEP61 inhibition, there is an increase in the phosphorylation of PTP?, which translocates to lipid rafts and activates Fyn and subsequent NMDAR signaling. The results demonstrate a synergistic regulation of Fyn-NMDAR signaling by STEP61 and PTP?, which may contribute to the regulation of ethanol-related behaviors. NMDA, N-methyl-D-aspartate; PTP?, receptor-type protein tyrosine phosphatase alpha; STEP, STriatal-Enriched protein tyrosine Phosphatase.

Dataset Information

The Role of Protein Tyrosine Phosphatase (PTP)-1B in Cardiovascular Disease and Its Interplay with Insulin Resistance.

Publications

The Role of Protein Tyrosine Phosphatase (PTP)-1B in Cardiovascular Disease and Its Interplay with Insulin Resistance.

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