Signal transduction pathways regulated by arsenate and arsenite.
Arsenate and arsenite activate c-Jun N-terminal kinase (JNK), however, the mechanism by which this occurs is not known. By expressing inhibitory mutant small GTP-binding proteins, p21-activated kinase (PAK) and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinases (MEKKs), we have identified specific proteins that are involved in arsenate- and arsenite-mediated activation of JNK. We observe a distinct difference between arsenate and arsenite signaling, which demonstrates that arsenate and arsenite are capable of activating unique proteins. Both arsenate and arsenite activation of JNK requires Rac and Rho. Neither arsenate nor arsenite signaling was inhibited by a dominant-negative mutant of Cdc42 or Ras. Arsenite stimulation of JNK requires PAK, whereas arsenate-mediated activation of JNK was unaffected by inhibitory mutant PAK. Of the four MEKKs tested, only MEKK3 and MEKK4 are involved in arsenate-mediated activation of JNK. In contrast, arsenite-mediated JNK activation requires MEKK2, MEKK3 and MEKK4. These results better define the mechanisms by which arsenate and arsenite activate JNK and demonstrate differences in the regulation of signal transduction pathways by these inorganic arsenic species.
Porter
A C
AC
Department of Pharmacology, College of Pharmacy, The University of Arizona, Tucson, Arizona, AZ 85721-0207, USA.
Fanger
G R
GR
Vaillancourt
R R
RR
D001149:Arsenates / Q000494:pharmacology*; D018053:Arsenites / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048730:MAP Kinase Kinase Kinase 2; D048748:MAP Kinase Kinase Kinase 3; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D001149:Arsenates; D018053:Arsenites; D011994:Recombinant Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048730:MAP Kinase Kinase Kinase 2; D048748:MAP Kinase Kinase Kinase 3; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; C482618:MAP3K2 protein, human; C482625:MAP3K3 protein, human; C482779:MAP3K4 protein, human; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins