Dual leucine zipper-bearing kinase (DLK) activates p46SAPK and p38mapk but not ERK2.
Because the catalytic domain of dual leucine zipper-bearing kinase (DLK) bears sequence similarity to members of the mitogen-activated protein (MAP) kinase kinase kinase subfamily, this protein kinase was investigated for its ability to activate MAP kinase pathways. When transiently transfected and overexpressed in either COS 7 cells or NIH3T3 cells, wild type DLK potently activated p46(SAPK) (SAPK/JNK) but had no detectable effect in activating p42/44(MAPK). DLK also activated p38(mapk) when overexpressed in NIH3T3 cells. A catalytically inactive point mutant of DLK had no effect in these experiments. Consistent with its specificity in activating SAPK, DLK activated Elk-1 but not Sap1a-mediated transcription. In NIH3T3 cells, activation of SAPK by v-Src was markedly attenuated by coexpression of K185A, a catalytically inactive mutant of DLK, suggesting that this mutant could function in a dominant negative fashion in a pathway that leads from v-Src to SAPKs. In a series of co-transfection experiments, activation of p46(SAPK) by DLK was not inhibited by dominant negative mutants of Rac1 and Cdc42Hs, PAK65-R, or PAK65-A, but was attenuated by MEKK1(K432M). DLK(K185A) did not inhibit the ability of constitutively active MEKK1 to activate SAPK. Moreover, K185A significantly inhibited the activation of SAPK by constitutively active V-12 Rac1 and V-12 Cdc42Hs. These results suggest that DLK lies distal to Rac1 and/or Cdc42Hs but proximal to MEKK1 in a pathway leading from v-Src to SAPKs activation.
Fan
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G
Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0676, USA.
Merritt
S E
SE
Kortenjann
M
M
Shaw
P E
PE
Holzman
L B
LB
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002384:Catalysis; D002460:Cell Line; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; C494113:Elk1 protein, mouse; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12