Inhibition of T Cell Antigen Receptor Signaling by VHR-related MKPX (VHX), a New Dual Specificity Phosphatase Related to VH1 Related (VHR)

Scott Williams,Alexei Kharitonenkov,Adam Godzik,Joseph J. Merlo,Tomas Mustelin,James D. Posada,Andres Alonso,Songqing Na,Lukasz Jaroszewski,Natalya Kholod

doi:10.1074/jbc.m107653200

Scott Williams, Alexei Kharitonenkov + Show 8 more

Open Access

https://doi.org/10.1074/jbc.m107653200

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Abstract

A cDNA encoding a novel, human, dual-specific protein phosphatase was identified in the Incyte data base. The open reading frame predicted a protein of 184 amino acids related to the Vaccinia virus VH1 and human VH1-related (VHR) phosphatases. Expression VHR-related MKPX (VHX) was highest in thymus, but also detectable in monocytes and lymphocytes. A VHX-specific antiserum detected a protein with an apparent molecular mass of 19 kDa in many cells, including T lymphocytes and monocytes. VHX expression was not induced by T cell activation, but decreased somewhat at later time points. In vitro, VHX dephosphorylated the Erk2 mitogen-activated protein kinase with faster kinetics than did VHR, which is thought to be specific for Erk1 and 2. When expressed in Jurkat T cells, VHX had the capacity to suppress T cell antigen receptor-induced activation of Erk2 and of an NFAT/AP-1 luciferase reporter, but not an NF-kappaB reporter. Thus, VHX is a new member of the VH1/VHR group of small dual-specific phosphatases that act in mitogen-activated protein kinase signaling pathways.

Highlights

Phosphate is removed from phosphoproteins by two unrelated classes of protein phosphatases, the serine/threoninespecific phosphatases (PP1, PP2, etc.) and the protein tyrosine phosphatases (PTPases; reviewed in 1,2)
Identification of a Novel Dual Specificity Phosphatase, VHRrelated MKPX (VHX)—To identify novel protein phosphatases, the Incyte data base was screened for open reading frames encoding proteins with homology to PTPases
Since this name is already occupied by another unrelated dual-specific phosphatases (DSPs), MKP-X [15], known as Pyst2 [15, 24], B59 [25], or DUSP7 [26], we propose the name VHX for VHR-related MKPX for the new protein

Summary

Introduction

Phosphate is removed from phosphoproteins by two unrelated classes of protein phosphatases, the serine/threoninespecific phosphatases (PP1, PP2, etc.) and the protein tyrosine phosphatases (PTPases; reviewed in 1,2) The latter group uses a cysteine-based catalytic mechanism [3, 4] shared with a broader family of hydrolases, including phosphatases specific for phospholipids [5] and RNA [6]. The physiological function of VHR has remained somewhat unclear as it seems to be less efficient than many other MAP kinase-specific DSPs. We report the identification and initial characterization of a new human gene that encodes a DSP that is much more closely related to VH1 and VHR than to other DSPs. During our work, the nucleotide sequence and predicted open reading frame of this enzyme was deposited by others in GenBankTM under the name MKPX. We honor this name by proposing the acronym VHX for “VHR-related MKPX.”

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