Cytoplasmic SnoN in normal tissues and nonmalignant cells antagonizes TGF-β signaling by sequestration of the Smad proteins

Krakowski, Ari; Laboureau, Julien; Mauviel, Alain; Bissell, Mina J.; Luo, Kunxin

doi:10.1073/pnas.0504107102

Cited by 74 publications

(87 citation statements)

References 31 publications

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“…TGF-␤ pathway is strongly regulated at the level of Smad activation and nuclear translocation by different means. One mechanism involves Smad sequestration in the cytosol by proteins acting as repressors such as SnoN (31,32) or AKT (33,34). However, these proteins do not seem to participate in our system, because neither SnoN knockdown nor AKT inhibition with LY294002 was able to recover response to TGF-␤ in PTP1B-deficient cells (data not shown).…”

Section: Discussionmentioning

confidence: 82%

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

Ortiz

Caja

Bertrán

et al. 2012

Journal of Biological Chemistry

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Background: Tyrosine kinases and phosphatases modulate TGF-␤ signaling. Results: PTP1B deficiency attenuates TGF-␤-induced Smad phosphorylation correlating with suppression of growth inhibition and apoptosis, an effect that is reverted by genistein, and p65 or NOX1 knockdown. Conclusion: Lack of PTP1B impairs Smad activation in a NOX1 and NF-B-dependent manner. Significance: New insights are opened into the role of phosphatases in TGF-␤ signaling.

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Section: Discussionmentioning

confidence: 82%

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

Ortiz

Caja

Bertrán

et al. 2012

Journal of Biological Chemistry

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“…Examples of such Smad repressors are Ski and SnoN, as described in the previous section. According to the current model, Ski and SnoN seem to play dual roles in cancer progression, despite the fact that previous knowledge favored an oncogenic role for these proteins [88,[105][106][107]. The oncogenic potential of Ski and SnoN is known to be mediated by their ability to bind directly to nuclear Smad complexes and repress their transcriptional activities [85,[108][109][110][111].…”

Section: Relevance Of Stability Regulation Of Tgfβ Pathway Componentsmentioning

confidence: 92%

Regulating the stability of TGFβ receptors and Smads

et al. 2008

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Abbreviations: AIP4 (atrophin 1-interacting protein 4); BMP (bone morphogenetic protein); CHIP (carboxyl terminus of Hsc70-interacting protein); GSK3b (glycogen synthase kinase 3-b); HECT (homologous to E6-AP carboxyl terminus); MAPK (mitogen-activated protein kinase); NEDD4-2 (neural precursor cell expressed, developmentally downregulated 4-2); PIAS (protein inhibitor of activated Stat); Smurf (Smad ubiquitylation regulatory factor); STRAP (serine-threonine kinase receptorassociated protein); SUMO (small ubiquitin-like modifier); TbRI/TbRII (TGFb receptor type I and II); TGFb (transforming growth factor b); WWP1 (WW domain-containing protein 1); Ub (ubiquitin) npg Transforming growth factor β (TGFβ) controls cellular behavior in embryonic and adult tissues. TGFβ binding to serine/threonine kinase receptors on the plasma membrane activates Smad molecules and additional signaling proteins that together regulate gene expression. In this review, mechanisms and models that aim at explaining the coordination between several components of the signaling network downstream of TGFβ are presented. We discuss how the activity and duration of TGFβ receptor/Smad signaling can be regulated by post-translational modifications that affect the stability of key proteins in the pathway. We highlight links between these mechanisms and human diseases, such as tissue fibrosis and cancer. Regulating the stability of TGFβ receptors and Smads

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“…In addition to the up-regulation of Ski or SnoN expression, mislocalization may also contribute to malignant progression. SnoN is localized exclusively in the nucleus in cancer tissues, whereas in normal tissues and nontumorigenic cells, SnoN is predominantly cytoplasmic (42). The mechanism of transformation by Ski and SnoN was not defined until diverse studies converged on the conclusion that Ski/SnoN bind directly to the Smad3/4 complex and negatively regulate TGF-␤ signaling (39).…”

Section: Discussionmentioning

confidence: 99%

Impairment of Transforming Growth Factor β Signaling in Caveolin-1-deficient Hepatocytes

Mayoral

Valverde

Llorente

et al. 2010

Journal of Biological Chemistry

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signaling decreased in the absence of Cav-1 at the time that the transcriptional corepressor SnoN accumulates. Accordingly, the expression of TGF-␤ target genes, such as plasminogen activator inhibitor-1, is decreased due to the presence of the high levels of SnoN. Moreover, hepatocyte growth factor inhibited TGF-␤ signaling in the absence of Cav-1 by increasing SnoN expression. Taken together, these data might help to unravel why Cav-1-deficient mice exhibit an accelerated liver regeneration after partial hepatectomy and add new insights on the molecular mechanisms controlling the initial commitment to hepatocyte proliferation.

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Cytoplasmic SnoN in normal tissues and nonmalignant cells antagonizes TGF-β signaling by sequestration of the Smad proteins

Cited by 74 publications

References 31 publications

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

Protein-tyrosine Phosphatase 1B (PTP1B) Deficiency Confers Resistance to Transforming Growth Factor-β (TGF-β)-induced Suppressor Effects in Hepatocytes

Regulating the stability of TGFβ receptors and Smads

Impairment of Transforming Growth Factor β Signaling in Caveolin-1-deficient Hepatocytes

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