Identification of c-Jun NH2-terminal Protein Kinase (JNK)-activating Kinase 2 as an Activator of JNK but Not p38

doi:10.1074/jbc.272.40.24751

Identification of c-Jun NH₂-terminal Protein Kinase (JNK)-activating Kinase 2 as an Activator of JNK but Not p38*

From the Department of Pathology, Division of Molecular and Cellular Pathology, the University of Alabama at Birmingham, Birmingham, Alabama 35294

Abstract

c-Jun NH₂-terminal protein kinase (JNK), a distant member of the mitogen-activated protein (MAP) kinase family, regulates gene expression in response to various extracellular stimuli. JNK is activated by JNK-activating kinase 1 (JNKK1), a dual specificity protein kinase that phosphorylates JNK on threonine 183 and tyrosine 185 residues. Here we show that JNKK2, a novel member of the MAP kinase kinase family, was phosphorylated and activated by MEKK1, a MAP kinase kinase kinase in the JNK signaling cascade. JNKK2 activity was also stimulated by constitutively active forms of Rac and Cdc42Hs, members of the Rho small GTP-binding protein family. Unlike JNKK1 that activates both JNK and p38 MAP kinases, JNKK2 stimulated only JNK. Transient transfection assays demonstrated that JNKK2 potentiated the stimulation of c-Jun transcriptional activity by MEKK1. The existence of multiple JNK-activating kinases may contribute to the specificity of the JNK signaling cascade.

Footnotes

↵* This work was supported by National Institutes of Health Grant CA73740, American Heart Association Scientist Development Grant 9630261N, American Cancer Society Grant IRG66-37, and the start-up fund from the Department of Pathology, University of Alabama at Birmingham (to A. L.).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) AF006689.
↵‡ To whom correspondence should be addressed. Tel.: 205-975-9225; Fax: 205-934-1775; E-mail: lin{at}vh.path.uab.edu.
↵1 The abbreviations used are: MAP, mitogen-activated protein; ERK, extracellular signal-related kinase; JNK, c-Jun NH₂-terminal protein kinase; JNKK, JNK-activating kinase; MEKK, MAP kinase kinase kinase; ATF, activating transcription factor; HA, hemagglutinin; CBSP, CSAID™-binding protein.
- Received June 12, 1997.
- Revision received August 11, 1997.