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

Abstract

SMAD and JNK cascades are essential components of the transforming growth factor-β (TGF-β) signaling machinery and are implicated in common transcriptional responses. However, the relationship of these pathways to one another downstream of the TGF-β receptor complex is unknown. We show that JNK is rapidly activated by TGF-β in a SMAD-independent manner and phosphorylates Smad3 outside its -SSXS motif. Smad3 phosphorylation by JNK facilitates both its activation by the TGF-β receptor complex and its nuclear accumulation. JNK regulates SMAD- and TGF-β-mediated transcriptional responses, yet JNK activators only partially stimulate transcriptional responses characteristic of TGF-β without coincident SMAD pathway activation. These results suggest an interdependent relationship between the JNK and SMAD pathways in TGF-β-mediated transcription.