Abstract
The protein tyrosine phosphatases (PTPs) SHP2 and SHP1 are essential enzymes in many eukaryotic signaling pathways. They evolved sophisticated autoinhibition by the N-SH2 domain docking into the active site to inhibit substrate dephosphorylation, resulting in a predominantly closed equilibrium. Here, we investigate how the autoinhibition by SH2 domains evolved early in protein tyrosine phosphatases. We expressed, purified, and characterized several extant PTPs and resurrected ancestors. We determined when SH2-based autoinhibition appeared in our phylogeny by comparing the full-length basal activity to each phosphatase's catalytic domain activity. Additionally, we used the extant SHP2 and SHP1 activators GAB-1, IRS-1, PD-1, and BTLA to examine the evolutionary pathway for allosteric activators, such as their increasing specificity and effectiveness for extant PTPs compared to the ancestors. The evidence presented here revealed that protein tyrosine phosphates started with some level of basal autoinhibition and evolved pathways to fine-tune this regulation later with the bis-phosphorylated activators.