SMAD and JNK cascades are essential components of the transforming growth factor-␤ (TGF-␤) signaling machinery and are implicated in common transcriptional responses. However, the relationship of these pathways to one another downstream of the TGF-␤ receptor complex is unknown. We show that JNK is rapidly activated by TGF-␤ in a SMAD-independent manner and phosphorylates Smad3 outside its -SSXS motif. Smad3 phosphorylation by JNK facilitates both its activation by the TGF-␤ receptor complex and

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... its nuclear accumulation. JNK regulates SMAD-and TGF-␤-mediated transcriptional responses, yet JNK activators only partially stimulate transcriptional responses characteristic of TGF-␤ without coincident SMAD pathway activation. These results suggest an interdependent relationship between the JNK and SMAD pathways in TGF-␤-mediated transcription.