Protein tyrosine phosphatases (PTPs) play a critical role in mammalian signal transduction by catalyzing the dephosphorylation of phosphotyrosine residues. Aberrant PTP activity is associated with a wide variety of human diseases. Thus, targeted strategies that allow for the direct chemical activation of individual PTPs could prove beneficial for investigating the roles of PTP activities in specific signaling pathways and for the validation of PTPs as therapeutic targets. Our strategy for targeted activation seeks to discover strategic locations within PTPs to engineer cysteine-rich motifs that bind biarsenical small molecules such as FlAsH, ReAsH, AsCy3, and AsCy5. A successfully engineered activatable PTP would maintain wild-type activity levels in the absence of biarsenical and would demonstrate a substantial increase in activity upon addition of biarsenical. A generalizable approach for PTP activation has been developed by creating a tri-cysteine binding motif to replace non-conserved residues of the catalytically important WPD loop. Activatable WPD loop mutants studied thus far include the PTP domains of PTP1B, TCPTP, HePTP, PTPκ, and SHP2. Targeted activation has also been achieved by replacing amino acids residues with biarsenical-binding motifs in the autoinhibitory domain of full length SHP2 such that the open, active conformation of SHP2 is preferred upon ligand binding. Current work focuses on the optimization of both of these activation strategies.

Biarsenical-induced activation of engineered protein tyrosine phosphatases (PTPs)

2019 Fall National Meeting

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