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The Role of Protein Tyrosine Phosphatase (PTP)-1B in Cardiovascular Disease and Its Interplay with Insulin Resistance - PubMed Skip to main page content
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Review
. 2019 Jul 17;9(7):286.
doi: 10.3390/biom9070286.

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

Shahenda S Abdelsalam  1 , Hesham M Korashy  1 , Asad Zeidan  2 , Abdelali Agouni  3
Affiliations
Review

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

Shahenda S Abdelsalam et al. Biomolecules. .

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.

Keywords: PTP1B; cardiovascular disease; diabetes; endothelial dysfunction; insulin resistance.

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Conflict of interest statement

Authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Nitric oxide (NO)-mediated physiological actions. NO has various physiological roles mediating endothelial function and maintaining vascular homeostasis as being a vasodilatory, anti-inflammatory and anti-coagulant factor. VSMCs—vascular smooth muscle cells.
Figure 2
Figure 2
Insulin-mediated vascular actions. Insulin exerts vasodilatory and vasoconstricting actions in endothelial cells. Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3-K) branch of insulin signaling results in the phosphorylation (Ser1177) and subsequent activation of endothelial NO synthase (eNOS) stimulating NO production and release to induce vasodilation. Conversely, mitogen-activated protein kinase (MAPK) branch stimulates the production of endothelin-1 (ET-1) resulting in vasoconstriction. The negative regulatory actions of protein tyrosine phosphatase 1B (PTP1B) on insulin signaling response are indicated. Abbreviations: ERK, Extracellular signal-regulated kinases; MEK, MAPK ERK kinase, IRS-1, Insulin receptor substrate 1; Shc, Src homology domain.
Figure 3
Figure 3
Classical PTPs. The classical PTPs are a large family of tyrosine phosphatases composed of 37 family members that are subdivided based on their cellular localization into 16 non-transmembrane (cytosolic) PTPs and 21 transmembrane receptor-like PTPs. The non-transmembrane phosphatases have one catalytic domain while receptor-like PTPs have either one or two catalytic domains, having the intrinsic catalytic cysteine residue.
Figure 4
Figure 4
Leptin signaling. Binding of leptin results in the cross-linking of two adjacent receptors and the recruitment of Janus Kinase 2 (JAK2), which cross-phosphorylates each other. Activated JAKs phosphorylate tyrosine residues on the receptor allowing the docking of signal transducer and activator of transcription 3 (STAT3). JAKs phosphorylate STAT3, which then dissociate and dimerize. STAT3 dimers translocate to the nucleus where they upregulate the expression of anorexigenic protein pro-opiomelanocortin (POMC) and suppressing that of the orexigenic protein Agouti-related peptide (AgRP) mediating the regulation of energy expenditure, control of body weight and suppresses appetite. The negative regulatory actions of PTP1B on leptin signaling pathway are indicated.
Figure 5
Figure 5
Vascular endothelial growth factor (VEGF) signaling. Binding of VEGF-A to its receptor induces the receptor’s intrinsic tyrosine kinase, which induces autophosphorylation initiating the downstream signaling cascade. The downstream effectors include, PLCγ/PKC/ERK 1/2, PI3-K/Akt and p38 MAPK, which induce endothelial cell proliferation, survival and migration, respectively. The negative regulatory actions of PTP1B are indicated. BCL-2, B-cell lymphoma 2; BAD, BCL-2 agonist of cell death; eNOS, endothelial NO synthase; PI3-K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; PLCγ, phosphoinositide phospholipase C γ; PKC, Protein kinase C; ERK, Extracellular signal-regulated kinases; MAPK, mitogen-activated protein kinase.
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