thiophosphate intermediate is hydrolyzed, which is facilitated by the hydrogen bonding interactions of Gln262 and Asp181 that help to position in the water molecule at the desired site of nucleophillic attack. Regulation The Cys215 residue is essential for the enzymatic activity of PTP1B and similar cysteine residues are required for the activity of other members of the Class I PTP family. The thiolate anion form is needed for nucleophilic activity but it is susceptible to oxidation by reactive oxygen species (ROS) in the cell which would render the enzyme non-functional. This cysteine residue has been shown to oxidize under increased cellular concentrations of hydrogen peroxide (H2O2), produced in response to EGF and insulin signaling. The thiolate is oxidized to a sulfenic acid, which is converted to a sulfenyl amide after reacting with the adjacent Ser216 residue. This modification of the Cys215 residue prevents further oxidation of the residue which would be irreversible, and also induces a structural change in the cleft of the active site such that substrates may not bind. This oxidation can be reversed through reduction by glutathione and acts as a means of regulating PTP1B activity. Phosphorylation of the Ser50 residue has also been shown as a point of allosteric regulation of PTP1B, in which the phosphorylated state of the enzyme is inactive. Interactions PTPN1 has been shown to interact with BCAR1, epidermal growth factor receptor, Grb2 and IRS1. Vascular endothelial growth factor Receptor-2 and Vascular endothelial growth factor via PGC1-alpha/ERR-alpha Clinical Significance PTP1B has clinical implications in the treatment of type 2 diabetes as well as cancer. Gene knockout studies conducted in murine models has provided substantial evidence for the role PTP1B plays in the regulation of insulin signalling and the development of obesity. PTPN1 knockout mice kept on high fat diets showed a resistance to obesity and an increased degree of insulin sensitivity as compared to their wild-type counterparts. As such, the design and development of PTP1B inhibitors is a growing field of research for the treatment of type 2 diabetes and obesity. Although PTP1B is generally studied as a regulator of metabolism, some research suggest it may have a role in tumor development, though whether it is oncogenic or tumor suppressive is unclear, as there is data in support of both arguments. The high ROS concentrations within cancer cells provide an environment for potential constitutive inactivation of PTP1B and it has been shown in