Catalytic Activation of the Phosphatase MKP-3 by ERK2 Mitogen-Activated Protein Kinase

Science  22 May 1998:
Vol. 280, Issue 5367, pp. 1262-1265
DOI: 10.1126/science.280.5367.1262

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MAP kinase phosphatase–3 (MKP-3) dephosphorylates phosphotyrosine and phosphothreonine and inactivates selectively ERK family mitogen-activated protein (MAP) kinases. MKP-3 was activated by direct binding to purified ERK2. Activation was independent of protein kinase activity and required binding of ERK2 to the noncatalytic amino-terminus of MKP-3. Neither the gain-of-function Sevenmaker ERK2 mutant D319N nor c-Jun amino-terminal kinase–stress-activated protein kinase (JNK/SAPK) or p38 MAP kinases bound MKP-3 or caused its catalytic activation. These kinases were also resistant to enzymatic inactivation by MKP-3. Another homologous but nonselective phosphatase, MKP-4, bound and was activated by ERK2, JNK/SAPK, and p38 MAP kinases. Catalytic activation of MAP kinase phosphatases through substrate binding may regulate MAP kinase activation by a large number of receptor systems.

  • * Present address: Serono Pharmaceutical Research Institute, CH-1228, Plan-les-Ouates, Geneva, Switzerland.

  • Present Address: Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.

  • To whom correspondence should be addressed. E-mail: steve.arkinstall{at}

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