Protein tyrosine phosphatases (PTPs) are a super-family of enzymes responsible for dephosphorylating proteins involved in critical signaling pathways. Abnormal tyrosine phosphorylation has been implicated in a number of human diseases including cancer. Selective PTP inhibition is a notoriously difficult task due to a highly conserved active site found across the PTP family. To overcome this challenge, we are exploring the potential inhibitory function of a regulatory domain from a PTP. This regulatory domain comes from Src homology-2 domain-containing protein tyrosine phosphatase 2 (Shp2) and might be able to inhibit the PTP active site. In Shp2’s basal state, this regulatory domain, known as the N-SH2 domain, displays autoinhibition in which the N-SH2 domain gets wedged into the active site and prevents a substrate from binding. Recent studies have shown the N-SH2 domain can be removed, expressed independently, and still exhibit an inhibitory function. Since the PTP domain is highly conserved, this suggests that perhaps the inhibitory interaction between the N-SH2 domain and the PTP domain is not specific but a result of proximity. In which case, the isolated N-SH2 domain may be able to inhibit other PTPs. To recreate proximity, a tool known as chemically induced dimerization can be used to fuse protein modules to proteins of interest with the help of a bifunctional molecule. By testing the proximity effects of the N-SH2 domain, we will gain insight into generating inhibitory tools to control PTP activity.

Inhibition of protein-tyrosine phosphatases (PTPs) by chemically-induced dimerization

2019 Fall National Meeting

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