PTPN1

PTPN1, also known as PTP1B, is the gene encoding the protein tyrosine phosphatase non-receptor type 1. PTP1B is a cytosolic enzyme anchored to the cytoplasmic face of the endoplasmic reticulum by a C-terminal hydrophobic tail. The enzyme contains an N-terminal catalytic phosphatase domain, and its active-site signature is the HCX5R motif, with a catalytic cysteine essential for activity.

PTP1B acts as a negative regulator of signaling by dephosphorylating phosphotyrosine residues on a range of substrates. Its most studied role is the attenuation of insulin signaling through dephosphorylation of the insulin receptor and insulin receptor substrates, thereby influencing glucose homeostasis. It also participates in leptin signaling and modulates signaling from other receptor tyrosine kinases and non-receptor kinases such as JAK2. Through these actions, PTP1B affects cellular growth, metabolism, and energy balance. Expression is widespread and activity is tightly controlled; oxidation of the catalytic cysteine under oxidative stress inhibits activity and constitutes a reversible regulatory mechanism.

Clinical relevance: Altered PTPN1/PTP1B activity has been associated with metabolic diseases, including insulin resistance and type 2 diabetes, as well as obesity. In cancer research, PTP1B has been implicated in various tumors, with evidence for both tumor-promoting and tumor-suppressing roles depending on tissue type and signaling context.

Therapeutic targeting: PTP1B inhibitors have been developed to enhance insulin sensitivity and to probe cancer biology; several compounds have shown efficacy in preclinical models, though clinical development faces challenges with selectivity and potential side effects. One example of an inhibitor studied is trodusquemine, which acts as an allosteric PTP1B inhibitor in preclinical models.