Recent advances in PTP1B signaling in metabolism and cancer

Abstract

Protein tyrosine phosphorylation is one of the major post-translational modifications in eukaryotic cells and represents a critical regulatory mechanism of a wide variety of signaling pathways. Aberrant protein tyrosine phosphorylation has been linked to various diseases, including metabolic disorders and cancer. Few years ago, protein tyrosine phosphatases (PTPs) were considered as tumor suppressors, able to block the signals emanating from receptor tyrosine kinases. However, recent evidence demonstrates that misregulation of PTPs activity plays a critical role in cancer development and progression. Here, we will focus on PTP1B, an enzyme that has been linked to the development of type 2 diabetes and obesity through the regulation of insulin and leptin signaling, and with a promoting role in the development of different types of cancer through the activation of several pro-survival signaling pathways. In this review, we discuss the molecular aspects that support the crucial role of PTP1B in different cellular processes underlying diabetes, obesity and cancer progression, and its visualization as a promising therapeutic target.

Human Protein Tyrosine Phosphatase 1B (PTP1B): From Structure to Clinical Inhibitor Perspectives

“…PTP1B is a ubiquitous and abundant intracellular prototypic non-receptor tyrosine phosphatase that is recognized as a major negative regulator of numerous signaling cascades of metabolic and/or oncogenic relevance such as the insulin or epidermal growth factor (EGF) pathways [1][2][3]. In the case of insulin signaling, PTP1B dephosphorylates the insulin receptor (IR) as well as its substrates (insulin receptor substrates (IRS) proteins) [4].…”

“…In addition to insulin signaling, PTP1B also plays an important role in leptin signaling through dephosphorylation of JAK2, a downstream effector of the leptin receptor. This results in the inhibition of the synthesis of the appetite-stimulating hormone, neuropeptide Y [1]. In addition to its metabolic impact, several reports have pointed out the role of PTP1B in cancer serving both as a tumor suppressor or oncogene, depending on the cellular context [1,6].…”

“…This results in the inhibition of the synthesis of the appetite-stimulating hormone, neuropeptide Y [1]. In addition to its metabolic impact, several reports have pointed out the role of PTP1B in cancer serving both as a tumor suppressor or oncogene, depending on the cellular context [1,6]. In particular, mutations that affect PTP1B activity and subsequently different signaling pathways of oncogenic relevance such as the EGFR and JAK/STAT cascades were reported [1].…”

Biochemical, Enzymatic, and Computational Characterization of Recurrent Somatic Mutations of the Human Protein Tyrosine Phosphatase PTP1B in Primary Mediastinal B Cell Lymphoma

“…PTP1B is a ubiquitous non-receptor tyrosine phosphatase that serves as a major negative regulator of tyrosine phosphorylation cascades of metabolic importance such as insulin or leptin signaling [11,12]. In addition to its metabolic impact, mounting evidence points to a critical role of PTP1B in cancer, serving as a tumor suppressor or promoter depending on the context [13]. In particular, PTP1B plays a pivotal role in the modulation of relevant oncogenic signaling pathways such as the EGFR and the JAK/STAT cascades through tyrosine dephosphorylation of several protein effectors [13][14][15][16][17].…”

“…In addition to its metabolic impact, mounting evidence points to a critical role of PTP1B in cancer, serving as a tumor suppressor or promoter depending on the context [13]. In particular, PTP1B plays a pivotal role in the modulation of relevant oncogenic signaling pathways such as the EGFR and the JAK/STAT cascades through tyrosine dephosphorylation of several protein effectors [13][14][15][16][17]. Interestingly, genetic defects impacting these pathways and/or aberrant signaling are known in lymphoma [18][19][20].…”