Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway.
Mitogen-activated protein kinases (MAPKs) are components of sequential kinase cascades that are activated in response to a variety of extracellular signals. Members of the MAPK family include the extracellular response kinases (ERKs or p42/44(MAPK)), the c-Jun amino-terminal kinases (JNKs), and the p38/Hog 1 protein kinases. MAPKs are phosphorylated and activated ... by MAPK kinases (MKKs or MEKs), which in turn are phosphorylated and activated by MKK/MEK kinases (Raf and MKKK/MEKKs). We have isolated two cDNAs encoding splice variants of a novel MEK kinase, MEKK4. The MEKK4 mRNA is widely expressed in mouse tissues and encodes for a protein of approximately 180 kDa. The MEKK4 carboxyl-terminal catalytic domain is approximately 55% homologous to the catalytic domains of MEKKs 1, 2, and 3. The amino-terminal region of MEKK4 has little sequence homology to the previously cloned MEKK proteins. MEKK4 specifically activates the JNK pathway but not ERKs or p38, distinguishing it from MEKKs 1, 2 and 3, which are capable of activating the ERK pathway. MEKK4 is localized in a perinuclear, vesicular compartment similar to the Golgi. MEKK4 binds to Cdc42 and Rac; kinase-inactive mutants of MEKK4 block Cdc42/Rac stimulation of the JNK pathway. MEKK4 has a putative pleckstrin homology domain and a proline-rich motif, suggesting specific regulatory functions different from those of the previously characterized MEKKs.
Mesh Terms:
Alternative Splicing, Amino Acid Sequence, Animals, Base Sequence, Calcium-Calmodulin-Dependent Protein Kinases, Cloning, Molecular, Enzyme Activation, Fluorescent Antibody Technique, Indirect, Humans, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Mice, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Rabbits, Tumor Cells, Cultured, p38 Mitogen-Activated Protein Kinases
Alternative Splicing, Amino Acid Sequence, Animals, Base Sequence, Calcium-Calmodulin-Dependent Protein Kinases, Cloning, Molecular, Enzyme Activation, Fluorescent Antibody Technique, Indirect, Humans, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Mice, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Rabbits, Tumor Cells, Cultured, p38 Mitogen-Activated Protein Kinases
J. Biol. Chem.
Date: Mar. 28, 1997
PubMed ID: 9079650
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