Abstract
Heterotrimeric G protein G(q) stimulates the activity of p38 mitogen-activated protein kinase (MAPK) in mammalian cells. To investigate the signaling mechanism whereby alpha and betagamma subunits of G(q) activate p38 MAPK, we introduced kinase-deficient mutants of mitogen-activated protein kinase kinase 3 (MKK3), MKK4, and MKK6 into human embryonal kidney 293 cells. The activation of p38 MAPK by Galpha(q) and Gbetagamma was blocked by kinase-deficient MKK3 and MKK6 but not by kinase-deficient MKK4. In addition, Galpha(q) and Gbetagamma stimulated MKK3 and MKK6 activities. The MKK3 and MKK6 activations by Galpha(q), but not by Gbetagamma, were dependent on phospholipase C and c-Src. Galpha(q) stimulated MKK3 in a Rac- and Cdc42-dependent manner and MKK6 in a Rho-dependent manner. On the other hand, Gbetagamma activated MKK3 in a Rac- and Cdc42-dependent manner and MKK6 in a Rho-, Rac-, and Cdc42-dependent manner. Gbetagamma-induced MKK3 and MKK6 activations were dependent on a tyrosine kinase other than c-Src. These results suggest that Galpha(q) and Gbetagamma stimulate the activity of p38 MAPK by regulating MKK3 and MKK6 through parallel signaling pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Calcium-Calmodulin-Dependent Protein Kinases / physiology
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Cell Line
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GTP-Binding Protein alpha Subunits, Gq-G11
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GTP-Binding Protein beta Subunits*
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GTP-Binding Protein gamma Subunits*
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Heterotrimeric GTP-Binding Proteins / metabolism*
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Humans
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MAP Kinase Kinase 3
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MAP Kinase Kinase 4*
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MAP Kinase Kinase 6
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MAP Kinase Signaling System*
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Mitogen-Activated Protein Kinase Kinases / physiology
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Mitogen-Activated Protein Kinases / metabolism*
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Models, Biological
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Phosphatidylinositol 3-Kinases / physiology
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Protein-Tyrosine Kinases / metabolism*
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Protein-Tyrosine Kinases / physiology
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Proto-Oncogene Proteins p21(ras) / physiology
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Proto-Oncogene Proteins pp60(c-src) / physiology
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Receptor, Muscarinic M1
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Receptors, Muscarinic / metabolism
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Type C Phospholipases / physiology
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p38 Mitogen-Activated Protein Kinases
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rho GTP-Binding Proteins / physiology
Substances
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G-protein Beta gamma
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GTP-Binding Protein beta Subunits
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GTP-Binding Protein gamma Subunits
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Receptor, Muscarinic M1
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Receptors, Muscarinic
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Phosphatidylinositol 3-Kinases
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins pp60(c-src)
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 3
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MAP Kinase Kinase 4
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MAP Kinase Kinase 6
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MAP2K3 protein, human
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MAP2K4 protein, human
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MAP2K6 protein, human
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Mitogen-Activated Protein Kinase Kinases
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Type C Phospholipases
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GTP-Binding Protein alpha Subunits, Gq-G11
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Heterotrimeric GTP-Binding Proteins
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HRAS protein, human
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Proto-Oncogene Proteins p21(ras)
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rho GTP-Binding Proteins