Identification of a novel link between the protein kinase NDR1 and TGFÎ2 signaling in epithelial cells
نویسندگان
چکیده
Transforming growth factor-beta (TGFb) is a secreted polypeptide that plays essential roles in cellular development and homeostasis. Although mechanisms of TGFb-induced responses have been characterized, our understanding of TGFb signaling remains incomplete. Here, we uncover a novel function for the protein kinase NDR1 (nuclear Dbf2-related 1) in TGFb responses. Using an immunopurification approach, we find that NDR1 associates with SnoN, a key component of TGFb signaling. Knockdown of NDR1 by RNA interference promotes the ability of TGFb to induce transcription and cell cycle arrest in NMuMG mammary epithelial cells. Conversely, expression of NDR1 represses TGFb-induced transcription and inhibits the ability of TGFb to induce cell cycle arrest in NMuMG cells. Mechanistically, we find that NDR1 acts in a kinase-dependent manner to suppress the ability of TGFb to induce the phosphorylation and consequent nuclear accumulation of Smad2, which is critical for TGFb-induced transcription and responses. Strikingly, we also find that TGFb reciprocally regulates NDR1, whereby TGFb triggers the degradation of NDR1 protein. Collectively, our findings define a novel and intimate link between the protein kinase NDR1 and TGFb signaling. NDR1 suppresses TGFb-induced transcription and cell cycle arrest, and counteracting NDR1’s negative regulation, TGFb signaling induces the downregulation of NDR1 protein. These findings advance our understanding of TGFb signaling, with important implications in development and tumorigenesis. Citation: Pot I, Patel S, Deng L, Chandhoke AS, Zhang C, et al. (2013) Identification of a Novel Link between the Protein Kinase NDR1 and TGFb Signaling in Epithelial Cells. PLoS ONE 8(6): e67178. doi:10.1371/journal.pone.0067178 Editor: Srinivasa M. Srinivasula, IISER-TVM, India Received December 13, 2012; Accepted May 14, 2013; Published June 26, 2013 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This work is supported by grants from the Alberta Cancer Foundation (ACF) and the Canadian Institutes of Health Research to S.B., a National Institutes of Health grant to A.B. (NS041021), Alberta Heritage Medical Foundation for Research (AHFMR) and ACF postdoctoral fellowships to I.P., and an ACF graduate studentship award to A.S.C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] . These authors contributed equally to this work.
منابع مشابه
Identification of a Novel Link between the Protein Kinase NDR1 and TGFβ Signaling in Epithelial Cells
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 app...
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