Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption.
Targeted disruption of the gene encoding MEK kinase 1 (MEKK1), a mitogen-activated protein kinase (MAPK) kinase kinase, defined its function in the regulation of MAPK pathways and cell survival. MEKK1(-/-) embryonic stem cells from mice had lost or altered responses of the c-Jun amino-terminal kinase (JNK) to microtubule disruption and cold stress but activated JNK normally in response to heat shock, anisomycin, and ultraviolet irradiation. Activation of JNK was lost and that of extracellular signal-regulated protein kinase (ERK) was diminished in response to hyperosmolarity and serum factors in MEKK1(-/-) cells. Loss of MEKK1 expression resulted in a greater apoptotic response of cells to hyperosmolarity and microtubule disruption. When activated by specific stresses that alter cell shape and the cytoskeleton, MEKK1 signals to protect cells from apoptosis.
Yujiri
T
T
Program in Molecular Signal Transduction, Division of Basic Sciences, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Sather
S
S
Fanger
G R
GR
Johnson
G L
GL
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D048429:Cell Size; D002470:Cell Survival; D004789:Enzyme Activation; D018390:Gene Targeting; D048031:JNK Mitogen-Activated Protein Kinases; D008246:Lysophospholipids / Q000494:pharmacology; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D015739:Nocodazole / Q000494:pharmacology; D009994:Osmolar Concentration; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013234:Stem Cells; D013696:Temperature; D014162:Transfection; D014466:Ultraviolet Rays
D008246:Lysophospholipids; D011994:Recombinant Proteins; D000841:Anisomycin; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D015739:Nocodazole