PTP1B

PTP1B, or protein tyrosine phosphatase 1B, is a non-receptor protein tyrosine phosphatase encoded by the PTPN1 gene in humans. It functions as a negative regulator of signal transduction by removing phosphate groups from phosphorylated tyrosine residues on signaling proteins.

PTP1B is a cytosolic enzyme anchored to the cytoplasmic face of the endoplasmic reticulum by a C-terminal hydrophobic tail. Its catalytic domain comprises about 300 amino acids and contains the conserved active-site motif HCXAGXXR(S/T)G; catalysis relies on a catalytic cysteine and a WPD loop that acts as an acid/base catalyst.

Substrates include the insulin receptor and insulin receptor substrate-1 (IRS-1), making PTP1B a key negative regulator of insulin signaling. It also modulates leptin signaling by dephosphorylating JAK2 and the leptin receptor. Through these actions it participates in the regulation of glucose homeostasis and energy balance. PTP1B also affects other receptors and kinases in growth factor pathways, with activity that intersects cell adhesion and migration signaling.

Clinical and research significance: because of its central role in metabolic signaling, PTP1B has been pursued as a therapeutic target for obesity and type 2 diabetes. Several small-molecule inhibitors have been developed, including allosteric compounds, but none have regulatory approval due to issues with potency, selectivity, and safety. In cancer, PTP1B can act as either a tumor suppressor or a promoter, depending on tissue context and signaling environment.

Expression and regulation: PTPN1 is broadly expressed, with higher levels in insulin-responsive tissues such as liver, muscle, and adipose tissue, and its expression is modulated by nutritional and hormonal signals.