MKK7 Is A Stress-activated Mitogen-activated Protein Kinase Kinase Functionally Related to hemipterous

doi:10.1074/jbc.272.40.24994

MKK7 Is A Stress-activated Mitogen-activated Protein Kinase Kinase Functionally Related to *hemipterous**

From the ^‡Fred Hutchinson Cancer Research Center, A2-025, Seattle, Washington 98109, the ^§Department of Biochemistry, University of Washington, Seattle, Washington 98195, and the ^‖Centre de Biologie du Developpement, Unite Mixte de Recherche 5547, Centre National de la Recherche Scientifique, 118 route de Narbonne, 31062 Toulouse Cedex, France

Abstract

Exposure of mammalian cells to stressful stimuli results in activation of the c-Jun NH₂-terminal kinase (JNK)/stress-activated protein kinases (SAPKs), a family of protein kinases related to mitogen-activated protein (MAP) kinase. JNK/SAPKs are activated by specific MAP kinase kinases (MKKs), one of which, MKK4/SEK1, has been characterized extensively. InDrosophila, the JNK/SAPK Basket (Bsk) and the MKK Hemipterous (Hep), are important for embryonic development. Loss of function of either gene inhibits dorsal closure, a morphogenetic movement in which the edges of the embryonic ectoderm move together over the amnioserosa. There is evidence that the Rho GTPases Rac and Cdc42 are also required for dorsal closure, suggesting that Rac or Cdc42 may regulate Hep and Bsk. We have identified MKK7, a murine homolog of Hep. MKK7 functionally rescues hep mutant flies. In fibroblasts, MKK7 is activated by stress and by the GTPase Rac1. MKK7 directly phosphorylates and activates JNK/SAPK. Thus, MKK7 is a homolog of hep and functions in a conserved signaling pathway involving JNK/SAPK and the GTPase Rac1.

Footnotes

↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) U74463 (MKK7a) and U74464 (MKK7b).
↵¶ Supported by an National Science Foundation predoctoral fellowship.
↵** Supported by the Ministere de l’Education Nationale, de l’Enseignement Superieur et de la Recherche (MENESR).
↵‡ Supported by a mentored-based Diabetes fellowship.
↵§§ Supported by the Center National de la Recherche Scientifique (CNRS) and Association pour la Recherche sur le Cancer (ARC).
↵¶¶ Supported by the National Institutes of Health. To whom correspondence should be addressed. Tel.: 206-667-4454; Fax: 206-667-6522; E-mail: jcooper{at}fhcrc.org.
↵1 The abbreviations used are: MAP kinase, mitogen-activated protein kinase; JNK, c-Jun NH₂-terminal kinase; SAPK, stress-activated protein kinase; MKK, MAP kinase kinase; SEK1, SAPK/ERK kinase; ERK, extracellular signal regulated kinase; PCR, polymerase chain reaction; XMEK2, Xenopus MAPK/ERK kinase; GST, glutathione S-transferase; HA, hemagglutinin; SH3, Src homology 3; ATF2, activating transcription factor 2; PDGF, platelet-derived growth factor; kb, kilobase(s); PAGE, polyacrylamide gel electrophoresis; Pipes, 1,4-piperazinediethanesulfonic acid.
↵2 P. M. Holland, unpublished results.
↵3 A. Finch, P. Holland, J. Cooper, J. Saklatvala, and M. Kracht, submitted for publication.
- Received June 24, 1997.
- Revision received August 8, 1997.