Identification of a Novel Link between the Protein Kinase NDR1 and TGF? Signaling in Epithelial Cells.

ABSTRACT: Transforming growth factor-beta (TGF?) is a secreted polypeptide that plays essential roles in cellular development and homeostasis. Although mechanisms of TGF?-induced responses have been characterized, our understanding of TGF? signaling remains incomplete. Here, we uncover a novel function for the protein kinase NDR1 (nuclear Dbf2-related 1) in TGF? responses. Using an immunopurification approach, we find that NDR1 associates with SnoN, a key component of TGF? signaling. Knockdown of NDR1 by RNA interference promotes the ability of TGF? to induce transcription and cell cycle arrest in NMuMG mammary epithelial cells. Conversely, expression of NDR1 represses TGF?-induced transcription and inhibits the ability of TGF? to induce cell cycle arrest in NMuMG cells. Mechanistically, we find that NDR1 acts in a kinase-dependent manner to suppress the ability of TGF? to induce the phosphorylation and consequent nuclear accumulation of Smad2, which is critical for TGF?-induced transcription and responses. Strikingly, we also find that TGF? reciprocally regulates NDR1, whereby TGF? triggers the degradation of NDR1 protein. Collectively, our findings define a novel and intimate link between the protein kinase NDR1 and TGF? signaling. NDR1 suppresses TGF?-induced transcription and cell cycle arrest, and counteracting NDR1's negative regulation, TGF? signaling induces the downregulation of NDR1 protein. These findings advance our understanding of TGF? signaling, with important implications in development and tumorigenesis.

SUBMITTER: Pot I 

PROVIDER: S-EPMC3694053 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature