Protein tyrosine phosphatase 1B in metabolic and cardiovascular diseases: from mechanisms to therapeutics

Abstract

Protein Tyrosine Phosphatase 1B (PTP1B) has emerged as a significant regulator of metabolic and cardiovascular disease. It is a non-transmembrane protein tyrosine phosphatase that negatively regulates multiple signaling pathways integral to the regulation of growth, survival, and differentiation of cells, including leptin and insulin signaling, which are critical for development of obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. Given PTP1B's central role in glucose homeostasis, energy balance, and vascular function, targeted inhibition of PTP1B represents a promising strategy for treating these diseases. However, challenges, such as off-target effects, necessitate a focus on tissue-specific approaches, to maximize therapeutic benefits while minimizing adverse outcomes. In this review, we discuss molecular mechanisms by which PTP1B influences metabolic and cardiovascular functions, summarize the latest research on tissue-specific roles of PTP1B, and discuss the potential for PTP1B inhibitors as future therapeutic agents.

Keywords: cardiovascular disease; diabetes; insulin resistance; obesity; protein tyrosine phosphatase 1B (PTP1B); therapeutics.

Figure 1

Role of PTP1B in the insulin signaling cascade. Binding of Insulin receptor substrates (IRS) activates the phosphatidylinositol-4,5-biphosphate-3-kinase (PI3K)/AKT pathway which is crucial for cellular survival and the mitogen-activated protein kinase (MAPK) pathway that is responsible for cell differentiation and cell growth. PTP1B negatively regulates insulin signaling by directly dephosphorylating both the IR and IRS1/2, reducing the activity of downstream effectors, including the PI3K/AKT pathway, reducing cellular glucose uptake. IR, insulin receptor; IGF, insulin-like growth factor; PTP1B, protein tyrosine phosphatase 1B; MEK, MAPK ERK kinase; ERK, extracellular signal-regulated kinases; p85 and p110, subunits of PI3K; PIP, phosphatidylinositol phosphate; PDK, protein dependent kinase. Image created with BioRender.com.

Figure 2

Role of PTP1B in regulation of the leptin signaling pathway. Binding of leptin to the leptin receptor initiates the recruitment of Janus Kinase 2 (JAK2) and their auto-phosphorylation process. Phosphorylated JAK2 then phosphorylates the tyrosine residue on the receptor which allows the docking of signal transducer and activator of transcription 3 (STAT3). STAT3 promotes the activation of Proopiomelanocortin (POMC) and inhibits the expression of agouti-related protein (AgRP). PTP1B suppresses the phosphorylation level of JAK2 and leptin receptors and henceforth STAT3 docking. PTP1B: protein tyrosine phosphatase 1B. Image created with BioRender.com.

Figure 3

Vascular endothelial growth factor (VEGF) signaling. Binding of VEGF to VEGFR induces its tyrosine phosphorylation, which is followed by the activation of downstream effectors including PLCγ/PKC/ERK1/2, PI3K/AKT, Src, p38 and FAK/Paxillin. PTP1B binds to VEGFR and directly dephosphorylates VEGFR. PTP1B directly binds to platelet-derived growth factor receptor (PDGFR), inducing motility in smooth muscle cells (SMCs). The fibroblast growth factor receptor (FGFR1) directly phosphorylates pyruvate kinase M2 (PKM2), PTP1B dephosphorylates PKM2 and regulates myocyte regeneration. VEGF, vascular endothelial growth factor; PTP1B, protein tyrosine phosphatase 1B; FAK, focal adhesion kinase; PI3K, phosphatidylinositol 3-kinases; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; PLCy, phospho-lipase C gamma; PKC, protein kinase C; ERK1/2, extracellular signal-regulated kinase 1/2; PKM2, pyruvate kinase M2. Image created with BioRender.com.