The transmembrane protein tyrosine phosphatase alpha dephosphorylates the insulin receptor in intact cells

Protein tyrosine phosphatases (PTPs) are key regulators in a variety of signal transduction processes. However, substrates for most PTPs have not been determined. In a previous report, we demonstrated that in a transient expression system the intracellular phosphatases PTPs 1B and TC preferentially dephosphorylated the precursor form of several receptor tyrosine kinases. In this paper we show that the dephosphorylation of kinase precursors is a specific feature of PTPs 1B and TC that is not shared by two other intracellular PTPs, PTPH1 or SHP-1. By contrast, the receptor phosphatase PTP alpha preferentially dephosphorylated the beta-subunit of the insulin receptor localized on the cell surface. The insulin receptor was a better substrate for PTP alpha than for other receptor type PTPs. We conclude that the intracellular PTPs 1B and TC regulate the autophosphorylation of receptor tyrosine kinases during their posttranslational processing while receptor type PTPs regulate the mature, cell surface localized receptor tyrosine kinases.