Abstract
SMAD and JNK cascades are essential components of the transforming growth factor-beta (TGF-beta) signaling machinery and are implicated in common transcriptional responses. However, the relationship of these pathways to one another downstream of the TGF-beta receptor complex is unknown. We show that JNK is rapidly activated by TGF-beta in a SMAD-independent manner and phosphorylates Smad3 outside its -SSXS motif. Smad3 phosphorylation by JNK facilitates both its activation by the TGF-beta receptor complex and its nuclear accumulation. JNK regulates SMAD- and TGF-beta-mediated transcriptional responses, yet JNK activators only partially stimulate transcriptional responses characteristic of TGF-beta without coincident SMAD pathway activation. These results suggest an interdependent relationship between the JNK and SMAD pathways in TGF-beta-mediated transcription.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Cells, Cultured
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DNA-Binding Proteins / physiology*
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JNK Mitogen-Activated Protein Kinases*
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase Kinases / physiology*
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Mitogen-Activated Protein Kinases / physiology
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Phosphorylation
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Plasminogen Activator Inhibitor 1 / biosynthesis
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Smad2 Protein
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Smad3 Protein
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Trans-Activators / physiology*
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Transcription, Genetic / drug effects*
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Transforming Growth Factor beta / pharmacology*
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rhoA GTP-Binding Protein / physiology
Substances
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DNA-Binding Proteins
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Plasminogen Activator Inhibitor 1
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Smad2 Protein
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Smad3 Protein
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Trans-Activators
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Transforming Growth Factor beta
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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rhoA GTP-Binding Protein