title: Identification of a Novel Link between the Protein Kinase NDR1 and TGFβ Signaling in Epithelial Cells.
abstract: Transforming growth factor-beta (TGFβ) is a secreted polypeptide that plays essential roles in cellular development and homeostasis. Although mechanisms of TGFβ-induced responses have been characterized, our understanding of TGFβ signaling remains incomplete. Here, we uncover a novel function for the protein kinase NDR1 (nuclear Dbf2-related 1) in TGFβ responses. Using an immunopurification approach, we find that NDR1 associates with SnoN, a key component of TGFβ signaling. Knockdown of NDR1 by RNA interference promotes the ability of TGFβ to induce transcription and cell cycle arrest in NMuMG mammary epithelial cells. Conversely, expression of NDR1 represses TGFβ-induced transcription and inhibits the ability of TGFβ to induce cell cycle arrest in NMuMG cells. Mechanistically, we find that NDR1 acts in a kinase-dependent manner to suppress the ability of TGFβ to induce the phosphorylation and consequent nuclear accumulation of Smad2, which is critical for TGFβ-induced transcription and responses. Strikingly, we also find that TGFβ reciprocally regulates NDR1, whereby TGFβ triggers the degradation of NDR1 protein. Collectively, our findings define a novel and intimate link between the protein kinase NDR1 and TGFβ signaling. NDR1 suppresses TGFβ-induced transcription and cell cycle arrest, and counteracting NDR1's negative regulation, TGFβ signaling induces the downregulation of NDR1 protein. These findings advance our understanding of TGFβ signaling, with important implications in development and tumorigenesis.
authors.affiliation: Southern Alberta Cancer Research Institute and Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pot
authors.forename: Shachi
authors.initials: S
authors.lastname: Patel
authors.forename: Lili
authors.initials: L
authors.lastname: Deng
authors.forename: Amrita Singh
authors.initials: AS
authors.lastname: Chandhoke
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Azad
authors.initials: A
authors.lastname: Bonni
authors.forename: Shirin
authors.initials: S
authors.lastname: Bonni
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C060615:SKIL protein, human; C491614:STK38 protein, human