Research ArticleBiochemistry

Phosphorylation of the phosphatase PTPROt at Tyr399 is a molecular switch that controls osteoclast activity and bone mass in vivo

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Science Signaling  08 Jan 2019:
Vol. 12, Issue 563, eaau0240
DOI: 10.1126/scisignal.aau0240

A phosphoswitch for a phosphatase

The receptor-type tyrosine phosphatase PTPROt either stimulates or inhibits the kinase Src in different contexts. In osteoclasts, PTPROt stimulates Src activity, which promotes bone resorption. Roth et al. described mice lacking PTPROt entirely and mice lacking a putative phosphorylation site at the C terminus of PTPROt, Tyr399. Phenotypic analyses of the mice, combined with experiments in osteoclasts derived from them and in cultured cells, demonstrated that Tyr399 is a phosphoswitch that controls PTPROt activity toward Src. When Tyr399 was not phosphorylated, PTPROt dephosphorylated Src at an activating site, thus inhibiting Src activity. When PTPROt Tyr399 was phosphorylated, PTPROt recruited Src through the adaptor protein Grb2 and dephosphorylated an inhibitory site in Src, thereby activating the kinase. These findings explain how PTPROt both positively and negatively influences Src activity and suggest a potential switch function for C-terminal tyrosine residues in other tyrosine phosphatases.