A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK.
The stress-responsive p38 and JNK MAPK pathways regulate cell cycle and apoptosis. A human MAPKKK, MTK1 (= MEKK4), mediates activation of both p38 and JNK in response to environmental stresses. Using a yeast two-hybrid method, three related proteins, GADD45alpha (= GADD45), GADD45, (= MyD118), and GADD45gamma, were identified that bound to an N-terminal domain of MTK1. These proteins activated MTK1 kinase activity, both in vivo and in vitro. The GADD45-like genes are induced by environmental stresses, including MMS, UV, and gamma irradiation. Expression of the GADD45-like genes induces p38/JNK activation and apoptosis, which can be partially suppressed by coexpression of a dominant inhibitory MTK1 mutant protein. We propose that the GADD45-like proteins mediate activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses.
Takekawa
M
M
Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Saito
H
H
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D005810:Multigene Family; D010449:Peptide Mapping; D011485:Protein Binding; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013312:Stress, Physiological / Q000378:metabolism*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases; D000097642:GADD45 Proteins
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D047908:Intracellular Signaling Peptides and Proteins; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases; D011506:Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000097642:GADD45 Proteins; C485654:GADD45G protein, human; C482779:MAP3K4 protein, human