Acts as a negative regulator of insulin receptor (IR) signaling and is involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver (By similarity). Plays a critical role in signaling transduction pathways and phosphoprotein network topology in red blood cells. May play a role in osteoclast formation and function. Acts as a negative regulator of insulin receptor (IR) signaling in skeletal muscle. Regulates insulin-induced tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate 1 (IRS-1), phosphorylation of protein kinase B and glycogen synthase kinase-3 and insulin induced stimulation of glucose uptake. Isoform 1 and isoform 2 act as a negative regulator of FceRI-mediated signal transduction leading to cytokine production and degranulation, most likely by acting at the level of SYK to affect downstream events such as phosphorylation of SLP76 and LAT and mobilization of Ca(2+). H2O + O-phospho-L-tyrosyl-[protein] = L-tyrosyl-[protein] + phosphate Inhibited by alendronate (ALN), orthovanadate, and phenylarsine oxide (PAO). Monomer (By similarity). Isoform 2: Homodimer. Can form oligomers. Dimerization is increased by oxidative stress and decreased by EGFR. Isoform 2 interacts with GRB2 (By similarity). Predominantly cytoplasmic. A small fraction is also associated with nucleus and membrane. Insulin can induce translocation to the membrane. Isoform 2 is expressed in the spleen and thymus (at protein level). Detected in fibroblasts, myeloid cells, macrophages, and T-cells but not in B-cell lines. Isoform 1 and isoform 2 are expressed predominantly in the brain, testes, and lungs, with lower levels present in lymph nodes, thymus, spleen, heart and mammary glands. Isoform 1 is expressed in osteoclasts and not in osteoblasts and its expression is related to osteoclast differentiation. It is also expressed in the erythrocytes. Isoform 2 is strongly expressed in skeletal muscle and L6 skeletal muscle cell line. Induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) and its induction is dependent upon PKC activity. The tyrosine-protein phosphatase 2 domain (D2) mediates dimerization. The extreme N- and C- termini of the D2 domain act to inhibit dimerization and removal of these sequences increases dimerization and inhibits enzyme activity. A catalytically active cytoplasmic form (p65) is produced by proteolytic cleavage of either isoform 1, isoform 2 or isoform 3. Phosphorylated on tyrosine residues by tyrosine kinase Neu. Phosphorylated on tyrosine residues by tyrosine kinase Neu. Glycosylated. Mice show greater insulin-induced tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) in the skeletal muscle. Antigen- and IgE-mediated passive systemic anaphylactic reactions are enhanced. Erythrocytes exhibit abnormal morphology, increased Ca(2+)-activated-K(+) channel activity and marked perturbation of the erythrocyte membrane tyrosine phosphoproteome. Produced by alternative promoter usage. Produced by alternative promoter usage. Produced by alternative initiation at Met-85 of isoform 1. Belongs to the protein-tyrosine phosphatase family. Receptor class 4 subfamily.