Multiple Regions of MAP Kinase Phosphatase 3 Are Involved in Its Recognition and Activation by ERK2

Bo Zhou, Li Wu, Kui Shen, Jialin Zhang, David S. Lawrence, Zhong Yin Zhang

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103 Scopus citations


Mitogen-activated protein kinase phosphatase 3 (MKP3) is a specific regulator of extracellular signal-regulated protein kinase 2 (ERK2). Association of ERK2 with MKP3 results in a powerful increase in MKP3 phosphatase activity. To determine the molecular basis of the specific ERK2 recognition by MKP3 and the ERK2-induced MKP3 activation, we have carried out a systematic mutational and deletion analysis of MKP3. Using activation-based and competition-based assays, we are able to quantitatively evaluate the contributions that residues/regions within MKP3 make to ERK2 binding and ERK2-induced MKP3 activation. Our results show that recognition and activation of MKP3 by ERK2 involves multiple regions of MKP3. Thus, the kinase interaction motif (KIM; residues 61-75) in MKP3 plays a major role (135-fold) for high affinity ERK2 binding. The most important residue in the KIM sequence of MKP3 is Arg65, which probably interacts with Asp319 in ERK2. In addition to KIM, a unique sequence conserved in cytosolic MKPs (residues 161-177 in MKP3) also contributes to ERK2 binding (15-fold). However, these two regions are not essential for ERK2-induced MKP3 activation. A third ERK2 binding site is localized in the C terminus of MKP3 (residues 348-381). Although deletion of this region or mutation of the putative ERK specific docking sequence 364FTAP367 in this region reduces MKP3's affinity for ERK2 by less than 10-fold, this region is absolutely required for ERK2-induced MKP3 activation.

Original languageEnglish (US)
Pages (from-to)6506-6515
Number of pages10
JournalJournal of Biological Chemistry
Issue number9
StatePublished - Mar 2 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry


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