Signaling crosstalk between TGFβ and Dishevelled/Par1b.

Crosstalk of signaling pathways is critical during metazoan development and adult tissue homeostasis. Even though the transforming growth factor-beta (TGF beta) transduction cascade is rather simple, in vivo responsiveness to TGF beta ligands is tightly regulated at several steps. As such, TGF beta represents a paradigm for how the activity of one signaling system is modulated by others. Here, we report an unsuspected regulatory step involving Dishevelled (Dvl) and Par1b (also known as MARK2). Dvl and Par1b cooperate to enable TGF beta/bone morphogenetic protein (BMP) signaling in Xenopus mesoderm development and TGF beta responsiveness in mammalian cells. Mechanistically, the assembly of the Par1b/Dvl3/Smad4 complex is fostered by Wnt5a. The association of Smad4 to Dvl/Par1 prevents its inhibitory ubiquitination by ectodermin (also known as transcriptional intermediary factor 1 gamma or tripartite motif protein 33). We propose that this crosstalk is relevant to coordinate TGF beta responses with Wnt-noncanonical and polarity pathways