UMMS Affiliation

Howard Hughes Medical Institute and Program in Molecular Medicine; Department of Biochemistry and Molecular Biology

Publication Date

1-16-1999

Document Type

Article

Subjects

Alternative Splicing; Amino Acid Sequence; Animals; COS Cells; Cell Line; Cell Nucleus; Chromosome Mapping; Cloning, Molecular; Cytoplasm; Enzyme Activation; Humans; In Situ Hybridization, Fluorescence; Isoenzymes; *MAP Kinase Kinase 4; MAP Kinase Kinase 7; MAP Kinase Kinase Kinases; Mice; *Mitogen-Activated Protein Kinase Kinases; Molecular Sequence Data; Protein Kinases; Protein-Serine-Threonine Kinases; Protein-Tyrosine Kinases; Sequence Homology, Amino Acid

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

The c-Jun NH2-terminal protein kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) group and is an essential component of a signaling cascade that is activated by exposure of cells to environmental stress. JNK activation is regulated by phosphorylation on both Thr and Tyr residues by a dual-specificity MAPK kinase (MAPKK). Two MAPKKs, MKK4 and MKK7, have been identified as JNK activators. Genetic studies demonstrate that MKK4 and MKK7 serve nonredundant functions as activators of JNK in vivo. We report here the molecular cloning of the gene that encodes MKK7 and demonstrate that six isoforms are created by alternative splicing to generate a group of protein kinases with three different NH2 termini (alpha, beta, and gamma isoforms) and two different COOH termini (1 and 2 isoforms). The MKK7alpha isoforms lack an NH2-terminal extension that is present in the other MKK7 isoforms. This NH2-terminal extension binds directly to the MKK7 substrate JNK. Comparison of the activities of the MKK7 isoforms demonstrates that the MKK7alpha isoforms exhibit lower activity, but a higher level of inducible fold activation, than the corresponding MKK7beta and MKK7gamma isoforms. Immunofluorescence analysis demonstrates that these MKK7 isoforms are detected in both cytoplasmic and nuclear compartments of cultured cells. The presence of MKK7 in the nucleus was not, however, required for JNK activation in vivo. These data establish that the MKK4 and MKK7 genes encode a group of protein kinases with different biochemical properties that mediate activation of JNK in response to extracellular stimuli.

Rights and Permissions

Citation: Mol Cell Biol. 1999 Feb;19(2):1569-81.

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Molecular and cellular biology

PubMed ID

9891090

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