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Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex

ABSTRACT: Cytokines of the TGF-β superfamily control essential cell fate decisions via receptor regulated SMAD (R-SMAD) transcription factors. Ligand-induced R-SMAD phosphorylation in the cytosol triggers their activation and nuclear accumulation. We determined how R-SMADs are inactivated by dephosphorylation in the cell nucleus to counteract signaling by TGF-β superfamily ligands. We showed that R-SMAD dephosphorylation is mediated by an inner nuclear membrane associated complex containing the scaffold protein MAN1 and the CTDNEP1/NEP1R1 phosphatase. Structural prediction, domain mapping and mutagenesis revealed that MAN1 binds independently to the CTDNEP1/NEP1R1 phosphatase and R-SMADs to promote their inactivation by dephosphorylation. Disruption of this complex led to nuclear accumulation of R-SMADs and aberrant signaling, even in the absence of TGF-β ligands. These findings establish CTDNEP1/NEP1R1 as the elusive R-SMAD phosphatase and reveal the mechanistic basis for TGF-β signaling inactivation and how this process is disrupted by disease-associated MAN1 mutations.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

SUBMITTER: Pedro Carvalho

LAB HEAD: Pedro Carvalho

PROVIDER: PXD051056 | Pride | 2025-01-28

REPOSITORIES: pride

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			Action	DRS
	20230414_MED_Oxford_Skyla_FlagCTDWT_1.raw	Raw
	20230414_MED_Oxford_Skyla_FlagCTDWT_2.raw	Raw
	20230414_MED_Oxford_Skyla_FlagCTDWT_3.raw	Raw
	20230414_MED_Oxford_Skyla_FlagEV_1.raw	Raw
	20230414_MED_Oxford_Skyla_FlagEV_1_20230414193239.raw	Raw

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Quantitative proteomics of the SMAD transcription factor family reveals IPO5 as a BMP Receptor-SMAD specific importin

Project description:Gene-specific transcription factors (GSTFs) control of gene transcription by DNA binding and specific protein complex recruitment, which regulates promoter accessibility for transcription initiation by RNA polymerase II. GSTFs that are frequently mutated in colon and rectal carcinomas are Suppressor of Mothers Against Decapentaplegic 2 (SMAD2) and SMAD4, which play an important role in the TGF-β signaling pathways controlling cell fate and proliferation (ref.). The SMAD protein family is a diverse and it can be divided into three subclasses: receptor activated SMADs, inhibitory SMADs and the common SMAD4 co-activator. To study protein interactors of the SMAD protein family we generated a quantitative proteomics pipeline that allows for inducible expression of GFP-tagged SMAD proteins followed by affinity purification and MS analysis. The nuclear importin IPO5 was identified as a novel interacting protein of SMAD1. Overexpression of IPO5 shows forced BMP R-SMAD nuclear localization confirming a functional relationship between BMP but not TGF-β R-SMADs and IPO5. Finally we provide evidence that the length of the lysine stretch in the NLS is involved in importin selection.

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p53 coordinates Wnt and TGF-β inputs on mesendoderm differentiation genes

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Smad3 binding regions in differentiated human progenitor epidermal keratinocytes (HPEK).

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HMCES counterbalances the transcriptional regulation of nodal/activin and BMP signaling in mESCs (ChIP-Seq)

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Interaction of Wnt signaling with Smad signaling during myogenic differentiation in mouse myoblast cells

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Transcription profiling timecourse of induced DACH1 expression in a human breast cancer cell line

Project description:The vertebrate homologues of Drosophila dachsund, DACH1 and DACH2, have been implicated as important regulatory genes in development. DACH1 plays a role in retinal and pituitary precursor cell proliferation and DACH2 plays a specific role in myogenesis. DACH proteins contain a domain (DS-domain) that is conserved with the proto-oncogenes Ski and Sno. Since the Ski/Sno proto-oncogenes repress AP-1 and SMAD signaling, we hypothesized that DACH1 might play a similar cellular function. Herein, DACH1 was found to be expressed in breast cancer cell lines and to inhibit TGF-beta induced apoptosis. DACH1 repressed TGF-beta induction of AP-1 and Smad signaling in gene reporter assays and repressed endogenous TGF-beta responsive genes by microarray analyses. DACH1 bound to endogenous NCoR and Smad4 in cultured cells and DACH1 co-localized with NCoR in nuclear dot-like structures. NCoR enhanced DACH1 repression and the repression of TGF-beta-induced AP-1 or Smad-signaling by DACH1 required the DACH1 DS domain. The DS-domain of DACH was sufficient for NCoR-binding at a Smad4-binding site. Smad4 was required for DACH1 repression of Smad signaling. In Smad4 null HTB-134 cells, DACH1 inhibited the activation of SBE-4 reporter activity induced by Smad2 or Smad3 only in the presence of Smad4. DACH1 participates in the negative regulation of TGF-beta signaling by interacting with NCoR and Smad4.

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Expression of TGFbeta Superfamily Growth Factors their Receptors and the Associated SMADs in Five Isolated Size matched Populations of Preantral Follicles from Normal Human Ovaries

Project description:In mammals, members of the transforming growth factor-beta (TGF-beta) superfamily are known to have key roles in the regulation of follicular growth and development. The aim of the study was to evaluate the expression of TGF-beta superfamily growth factors, their receptors and downstream SMAD signalling molecules during early human folliculogenesis. Human preantral follicles were enzymatically isolated from surplus ovarian tissue obtained from women having ovarian cortical tissue frozen for fertility preservation. A total of 348 human preantral follicles, ranging from 40 to 200 um in diameter, were isolated from ovarian tissue obtained from 15 women, aged 24M-^V34 years. Isolated preantral follicles were grouped according to diameter in five size-matched populations spanning the primordial, primary and secondary stage follicles, and analyzed by whole-genome microarray analysis. Selected proteins/genes were analysed by immunocytochemistry and quantitative RT-PCR. TGF-beta superfamily genes with overall highest mRNA expressions levels included growth differentiation factors 9 (GDF9), bone morphogenic protein-15 (BMP15), BMP6, BMP-receptor-2 (BMPR2), anti-MM-|llerian hormone receptor 2 (AMHR2), TGFbetaR3, inhibin-alpha (INHA), and intracellular SMAD3 and SMAD4. Moreover, genes which were differentially expressed from the primordial to the late secondary stage follicles included GDF9 (p<0.01), BMP15 (p<0.001), AMH (p<0.0001), INHBB (p<0.05), TGFbetaR3 (p<0.05) and SMAD4 (p<0.05). Collectively, these data indicate that the active TGF-beta superfamily pathways in early human folliculogenesis consist of primarily GDF9 combined with synergistic effects of BMP15 through the BMPR2 and intracellular activation of SMAD3 and SMAD4, and that AMH and Inhibin B are engaged in intrafollicular events from the onset of follicular growth.

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