Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription

SMAD and JNK cascades are essential components of the transforming growth f actor-beta (TGF-beta) signaling machinery and are implicated in common tran scriptional responses. However, the relationship of these pathways to one a nother 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 phos phorylates Smad3 outside its -SSXS motif. Smad3 phosphorylation by JNK faci litates both its activation by the TGF-beta receptor complex and its nuclea r accumulation. JNK regulates SMAD- and TGF-beta-mediated transcriptional r esponses, yet JNK activators only partially stimulate transcriptional respo nses characteristic of TGF-beta without coincident SMAD pathway activation. These results suggest an interdependent relationship between the JNK and S MAD pathways in TGF-beta-mediated transcription.