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Identification of Protein Tyrosine Phosphatases with Specificity for the Ligand-Activated Growth Hormone Receptor

Serono Pharmaceutical Research Institute (C.P., M.-L.C., S.W., X.E., M.G., F.A., R.H.v.H.), 1228 Plan-les-Ouates, Geneva, Switzerland; and Department of Cell Biology (G.S.), University Medical Center Utrecht, Heidelberglaan 100 AZU-G02.525, 3584 CX Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Rob Hooft van Huijsduijnen, Serono Pharmaceutical Research Institute 14, chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland. E-mail: rob.hooft{at}serono.com.

Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-ß, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR that had been produced by coexpression with a kinase in bacteria. We then used GH-induced, phosphorylated GH receptor, purified from overexpressing mammalian cells, in a Far Western-based approach to test whether these seven PTPs were also capable of recognizing ligand-induced, physiologically phosphorylated GHR. In this assay, only TC-PTP, PTP1B, PTP-H1, and SAP-1 interacted with the mature form of the phosphorylated GHR. In parallel, we show that these PTPs recognize very different subsets of the seven GHR tyrosines that are potentially phosphorylated. Finally, mRNA tissue distribution of these PTPs by RT-PCR analysis and coexpression of the wild-type PTPs to test their ability to dephosphorylate ligand-activated GHR suggest PTP-H1 and PTP1B as potential candidates involved in GHR signaling.

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