title: Signaling crosstalk between TGFβ and Dishevelled/Par1b.
abstract: Crosstalk of signaling pathways is critical during metazoan development and adult tissue homeostasis. Even though the transforming growth factor-beta (TGFβ) transduction cascade is rather simple, in vivo responsiveness to TGFβ ligands is tightly regulated at several steps. As such, TGFβ 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 TGFβ/bone morphogenetic protein (BMP) signaling in Xenopus mesoderm development and TGFβ 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 TGFβ responses with Wnt-noncanonical and polarity pathways.
authors.affiliation: Department of Biomedical Sciences, University of Padua, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Mamidi
authors.forename: M
authors.initials: M
authors.lastname: Inui
authors.forename: A
authors.initials: A
authors.lastname: Manfrin
authors.forename: S
authors.initials: S
authors.lastname: Soligo
authors.forename: E
authors.initials: E
authors.lastname: Enzo
authors.forename: M
authors.initials: M
authors.lastname: Aragona
authors.forename: M
authors.initials: M
authors.lastname: Cordenonsi
authors.forename: O
authors.initials: O
authors.lastname: Wessely
authors.forename: S
authors.initials: S
authors.lastname: Dupont
authors.forename: S
authors.initials: S
authors.lastname: Piccolo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002460:Cell Line; D000072261:Dishevelled Proteins; D004625:Embryo, Nonmammalian / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D054875:Ubiquitination; D051153:Wnt Proteins / Q000378:metabolism; D000071818:Wnt-5a Protein; D014981:Xenopus / Q000254:growth & development / Q000378:metabolism; D029867:Xenopus Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; C000606586:DVL1 protein, Xenopus; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D051901:Smad4 Protein; C511956:TRIM33 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D029867:Xenopus Proteins; C094670:MARK2 protein, human; D017346:Protein Serine-Threonine Kinases