MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo

doi:10.1016/0092-8674(93)90383-2

Cell

Volume 75, Issue 3, 5 November 1993, Pages 487-493

https://doi.org/10.1016/0092-8674(93)90383-2 Get rights and content

Abstract

Mitogenic stimulation of cells induces rapid and transient activation of MAP kinases. Here we report that a growth factor-inducible gene, 3CH134, encodes a dual specificity phosphatase that dephosphorylates and inactivates p42^MAPK both in vitro and in vivo. In vitro, 3CH134 protein dephosphorylates both T183 and Y185 in p42^MAPK. In serum-stimulated normal fibroblasts, the kinetics of inactivation of p42^MAPK coincides with the appearance of newly synthesized 3CH134 protein, and the protein synthesis inhibitor cycloheximide leads to persistent activation of MAP kinase. Expression of 3CH134 in COS cells leads to selective dephosphorylation of p42^MAPK from the spectrum of phosphotyrosyl proteins. 3CH134 blocks phosphorylation and activation of p42^MAPK mediated by serum, oncogenic Ras, or activated Raf, whereas the catalytically inactive mutant of the phosphatase, Cys-258→Ser, augments MAP kinase phosphorylation under similar conditions. The mutant 3CH134 protein also forms a physical complex with the phosphorylated form of p42^MAPK. These findings suggest that 3CH134 is a physiological MAP kinase phosphatase; we propose the name MKP-1 for this phosphatase.

References (28)

N.G. Ahn et al.
The mitogen-activated protein kinase activator
Curr. Opin. Cell Biol.
(1992)
W.J. Boyle et al.
Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates
Meth. Enzymol.
(1991)
C.M. Crews et al.
Extracellular signals and reversible protein phosphorylation: what to Mek of it all
Cell
(1993)
T.A.J. Haystead et al.
Okadaic acid mimics the action of insulin in stimulating protein kinase activity in isolated adipocytes
J. Biol. Chem.
(1990)
L.R. Howe et al.
Activation of the MAP kinase pathway by the protein kinase raf
Cell
(1992)
E. Nishida et al.
The MAP kinase cascade is essential for diverse signal transduction pathways
Trends Biochem. Sci.
(1993)
S.L. Pelech
Networking with protein kinases
Curr. Biol.
(1993)
J.S. Sanghera et al.
Tyrosyl phosphorylation and activation of the myelin basic protein kinase p44^mpk during sea star oocyte maturation
Biochim. Biophys. Acta
(1991)
L. Tsuda et al.
A protein kinase similar to MAP kinase activator acts downstream of the Raf kinase in Drosophila
Cell
(1993)
A. Ullrich et al.
Signal transduction by receptors with tyrosine kinase activity
Cell
(1990)

C.-F. Zheng et al.

Dephosphorylation and inactivation of the mitogen-activated protein kinase by a mitogen-induced thr/tyr protein phosphatase

J. Biol. Chem.

(1993)

D.R. Alessi et al.

The human CL100 gene encodes a Tyr/Thr-protein phosphatase which potently and specifically inactivates MAP kinase and suppresses its activation by oncogenic ras in Xenopus oocyte extracts

Oncogene

(1993)

N.G. Anderson et al.

Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase

Nature

(1990)

H. Charbonneau et al.

1002 protein phosphatases?

Annu. Rev. Cell Biol.

(1992)

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Cell

ArticleMKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo

Abstract

Curr. Opin. Cell Biol.

Meth. Enzymol.

Cell

J. Biol. Chem.

Cell

Trends Biochem. Sci.

Curr. Biol.

Biochim. Biophys. Acta

Cell

Cell

J. Biol. Chem.

The human CL100 gene encodes a Tyr/Thr-protein phosphatase which potently and specifically inactivates MAP kinase and suppresses its activation by oncogenic ras in Xenopus oocyte extracts

Oncogene

Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase

Nature

1002 protein phosphatases?

Annu. Rev. Cell Biol.

Article
MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo