PTP1B

Detailed Information

The PTPN1 (Protein Tyrosine Phosphatase Non-Receptor Type 1) gene is located on human chromosome 20q13.13 and encodes protein tyrosine phosphatase 1B (PTP1B), the first identified and cloned member of the protein tyrosine phosphatase family. The gene contains ten exons and, through alternative promoters and splicing, produces several transcript variants that encode two main isoforms: a full-length protein of 435 amino acids (50 kDa) and a shorter isoform of 398 amino acids (42 kDa). Structurally, PTP1B is composed of three essential domains: an N-terminal catalytic domain with a conserved PTP signature motif (HCXXGXXR), in which Cys215 is the indispensable nucleophilic residue; a C-terminal regulatory domain containing two proline-rich regions that mediate protein–protein interactions; and a terminal endoplasmic reticulum (ER)–targeting sequence (KDEL) that defines its subcellular localization.

Unlike receptor-type phosphatases, PTP1B is anchored to the ER surface through a C-terminal hydrophobic segment, enabling it to regulate a wide range of ER-associated signaling events. Its catalytic mechanism involves nucleophilic attack by the conserved cysteine residue on the phosphate group of phosphotyrosine, forming a covalent thiophosphate intermediate that is subsequently hydrolyzed to release inorganic phosphate. The enzymatic activity is tightly regulated by redox balance: the catalytic cysteine can be reversibly oxidized by reactive oxygen species (ROS) to sulfenic acid derivatives, transiently inhibiting activity and positioning PTP1B as a molecular sensor of oxidative stress.

Biological Functions and Signaling Networks

PTP1B acts as a critical negative regulator of intracellular signaling, playing essential roles in metabolic homeostasis, cell growth, and inflammation. In the insulin signaling pathway, PTP1B directly dephosphorylates activated insulin receptor β subunit tyrosine residues (notably Y1158, Y1162, and Y1163) as well as tyrosine-phosphorylated sites on insulin receptor substrate-1 (IRS1), thereby disrupting downstream PI3K-AKT and Ras-MAPK cascades. Knockout studies demonstrate that PTP1B-deficient mice exhibit enhanced insulin sensitivity and resistance to diet-induced obesity, establishing its central role in glucose metabolism.

In leptin signaling, PTP1B dephosphorylates JAK2 kinase at Y1007/Y1008, attenuating leptin receptor signaling in hypothalamic arcuate neurons. While leptin binding activates JAK2 and promotes STAT3 phosphorylation to drive anorexigenic signaling, PTP1B limits both the magnitude and duration of this pathway. Mice lacking PTP1B show heightened leptin sensitivity and increased energy expenditure, highlighting its dual role in energy balance.

PTP1B also regulates receptor tyrosine kinase (RTK) signaling and endocytosis. It modulates the trafficking of EGFR, PDGFR, and Met by dephosphorylating Rab5 effector proteins such as rabaptin-5, thereby influencing early endosomal fusion and receptor degradation. In atherosclerosis models, PTP1B overexpression in vascular smooth muscle cells disrupts PDGFRβ endocytosis, leading to sustained abnormal signaling and enhanced apoptosis, which contributes to plaque instability.

Moreover, PTP1B is involved in the unfolded protein response (UPR) during ER stress. It is activated by the IRE1α-JNK axis and dephosphorylates PERK, reducing eIF2α phosphorylation and dampening the ATF4-CHOP apoptotic pathway, thereby conferring cytoprotective effects. This adaptive role links PTP1B activity to the pathogenesis of metabolic and neurodegenerative disorders.

Figure 1. Effects of PTP1B on insulin and leptin signaling pathways, showing its inhibitory roles on insulin receptor and IRS1 phosphorylation, downstream PI3K/PDK1/AKT activation, and leptin receptor–JAK2–STAT3 signaling.(Delibegović M, et al., 2024)

Pathological Mechanisms in Disease

Metabolic Disorders

PTP1B is strongly implicated in the development of type 2 diabetes and obesity. In insulin-resistant states, its expression is upregulated in adipose tissue, largely driven by NF-κB–mediated transcription downstream of inflammatory cytokines such as TNF-α. This upregulation exacerbates insulin resistance, reinforcing hyperglycemia. In the liver, PTP1B suppresses insulin-induced AKT activation, impairing glucose uptake and glycogen synthesis, while in muscle it interferes with IRS1-associated PI3K signaling, reducing GLUT4 translocation. Clinical data confirm that skeletal muscle from patients with type 2 diabetes shows elevated PTP1B levels, correlating with fasting insulin and HOMA-IR indices.

Cancer

The role of PTP1B in cancer is context-dependent, displaying both oncogenic and tumor-suppressive functions. In breast cancer, PTP1B enhances HER2 signaling and promotes tumor progression. It is more frequently expressed in invasive ductal carcinoma and ductal carcinoma in situ compared with premalignant lesions or normal breast tissue. Mechanistically, PTP1B dephosphorylates inhibitory sites such as Y128 on p120Cas, thereby strengthening HER2-driven SRC and FAK signaling, which facilitates migration and invasion. Under hypoxic tumor microenvironments, PTP1B contributes to cellular adaptation by upregulating ubiquitin ligase RNF213, suppressing α-ketoglutarate–dependent dioxygenase activity, and altering histone methylation patterns to promote survival.

Conversely, in colorectal cancer and certain leukemias, PTP1B functions as a tumor suppressor by negatively regulating oncogenic RTKs such as EGFR and inhibiting STAT3 signaling. These contrasting effects highlight the complexity of PTP1B biology and underscore the need for precision-based patient stratification in therapeutic strategies.

Cardiovascular Disease

PTP1B contributes to atherosclerosis through two major mechanisms. In vascular smooth muscle cells, overexpression disrupts Rab5-mediated PDGFRβ endocytosis, leading to abnormal signaling and apoptosis, thereby weakening plaque stability. In endothelial cells, PTP1B reduces eNOS activity and nitric oxide bioavailability, impairing vascular function. In ApoE-deficient mice, pharmacological inhibition of PTP1B reduces lesion size and enhances plaque stability, suggesting a potential therapeutic avenue in atherosclerotic disease.

Therapeutic Implications

Given its diverse roles, PTP1B has emerged as a promising therapeutic target across metabolic, oncological, and cardiovascular diseases. In type 2 diabetes, small-molecule inhibitors such as Trodusquemine have reached phase II clinical evaluation. In breast cancer, allosteric inhibitors such as MSI-1436 are under preclinical and early clinical development. In atherosclerosis, peptide-based inhibitors have shown efficacy in animal models, while central delivery approaches are being explored for obesity treatment. Despite these advances, therapeutic development faces challenges due to the enzyme’s physiological importance, tissue-specific functions, and the need for selective inhibition strategies.