Regulation of apoptosis by alpha-subunits of G12 and G13 proteins via apoptosis signal-regulating kinase-1.
Many growth factors and G protein-coupled receptors activate mitogen-activated protein (MAP) kinase pathways. The MAP kinase pathways are involved in the regulation of the ubiquitous process of apoptosis or programmed cell death. Two related MAP kinase kinase kinases, apoptosis-signal regulating kinase 1 (ASK1) and MAP kinase kinase kinase 1 (MEKK1), stimulate c-Jun kinase (JNK) activity and induce apoptosis. Transient transfection of dominant negative and constitutively active components of the JNK pathway in COS-7 cells showed that two G protein subunits, Galpha12 and Galpha13, stimulated the JNK pathway in a ASK1- and MEKK1-dependent manner. Moreover, the mutationally activated Galpha12 and Galpha13 stimulated the kinase activity of ASK1. Both Galpha12 and Galpha13 employ small GTPases, Cdc42 and Rac1, to transduce signal to MEKK1 and, subsequently, to JNK. However, activation of JNK by Cdc42 and Rac1 did not require ASK1. Additionally, ASK1 and MEKK1 are involved in the apoptosis induced by Galpha12 and Galpha13. We conclude that Galpha12 and Galpha13 can induce apoptosis using two separate MAP kinase pathways; one is initiated by ASK1, and the other is initiated by MEKK1. Furthermore, Bcl-2 can block apoptosis induced by Galpha12 and Galpha13. This death-sparing function was associated with increased Bcl-2 phosphorylation, suggesting that phosphorylation of Bcl-2 may be a critical mechanism protecting cells from Galpha12- and Galpha13-induced apoptosis.
Department of Pharmacology, University of Illinois, Chicago, Illinois 60612, USA.
Y V
YV
Berestetskaya
M P
MP
Faure
H
H
Ichijo
T A
TA
Voyno-Yasenetskaya
D017209:Apoptosis / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D051960:GTP-Binding Protein alpha Subunit, Gi2; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein
D018797:Cell Cycle Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; 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; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; D019204:GTP-Binding Proteins; C498015:GNAI2 protein, human; D051960:GTP-Binding Protein alpha Subunit, Gi2; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020764:cdc42 GTP-Binding Protein