Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation

Yoon, Jeong Hwan; Sudo, Katsuko; Kuroda, Masahiko; Kato, Mitsuyasu; Lee, In Kyu; Han, Jin Soo; Nakae, Susumu; Imamura, Takeshi; Kim, Juryun; Ju, Ji Hyeon; Kim, Dae Kee; Matsuzaki, Koichi; Weinstein, Michael; Matsumoto, Isao; Sumida, Takayuki; Mamura, Mizuko

doi:10.1038/ncomms8600

Cited by 94 publications

(81 citation statements)

References 60 publications

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“…The results presented in the present study suggest distinct functions for Runx1 and Runx2 in Th Previous work has uncovered differential requirements for Smad transcription factors in differentiation of TGF-b1-dependent Th cell lineages. Smad2 is a positive regulator of Th9 and Th17 differentiation, whereas Smad3 is a negative regulator of Th17 development (32)(33)(34)54). Smad3 is also a positive regulator of Th9 development, but mechanisms by which Smad2 and Smad3 induce Th9 cells appear to be quite distinct (42,55).…”

Section: Discussionmentioning

confidence: 99%

Functions of Smad Transcription Factors in TGF-β1–Induced Selectin Ligand Expression on Murine CD4 Th Cells

Ebel

Kansas

2016

The Journal of Immunology

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Selectins are carbohydrate-binding adhesion molecules that control leukocyte traffic. Induction of selectin ligands on T cells is controlled primarily by cytokines, including TGF-β1, and requires p38α MAPK, but transcriptional mechanisms that underlie cytokine-driven selectin ligand expression are poorly understood. In this study, we show, using mice with conditional deletions of the TGF-β1–responsive transcription factors Smad2, Smad3, or Smad4, that induction of selectin ligands on CD4 cells in response to TGF-β1 requires Smad4 plus either Smad2 or Smad3. Analysis of CD4 cells from mice with only one functional Smad4 allele revealed a sharp gene dosage effect, suggesting the existence of a threshold of TGF-β1 signal strength required for selectin ligand induction. Both Smad4 plus either Smad2 or Smad3 were selectively required for induction of Fut7 and Gcnt1, glycosyltransferases critical for selectin ligand biosynthesis, but they were not required for St3gal4 or St3gal6 induction. Smad4 plus either Smad2 or Smad3 were also required for induction of Runx transcription factors by TGF-β1. Enforced expression of Runx2, but not Runx1 or Runx3, in Smad2/Smad3 doubly deficient CD4 cells restored selectin ligand expression to wild-type levels. In contrast, enforced expression of Runx1, Runx2, or Runx3 failed to restore differentiation of TGF-β1–dependent Th cell lineages, including Th17, Th9, and induced regulatory T cells. These results show that Smads are directly required for Th cell differentiation independent of Runx induction but only indirectly required via Runx2 for TGF-β1–induced selectin ligand induction on murine CD4 T cells.

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Section: Discussionmentioning

confidence: 99%

Functions of Smad Transcription Factors in TGF-β1–Induced Selectin Ligand Expression on Murine CD4 Th Cells

Ebel

Kansas

2016

The Journal of Immunology

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“…However, unlike their functional cooperation in transcription, the direct physical interaction between SMAD3 and STAT3 usually resulted in antagonizing each other. For instance, SMAD3 could bring PIAS3 to STAT3, which inhibits STAT3 DNA binding (17,27), whereas overexpression of hyperactive STAT3 traps SMAD3 from SMAD3-SMAD4 complex formation (16). It seems that the phosphorylation status of SMAD3 determines whether it inhibits or cooperates with STAT3 in transcription.…”

Section: Discussionmentioning

confidence: 99%

“…Physical interaction between SMAD3 and STAT3 was also reported (16). Moreover, unphosphorylated SMAD3 was also shown to be capable of recruiting PIAS3 (protein inhibitor of activated STAT3) to inhibit STAT3-dependent transcription by blocking DNA binding (17). To reconcile this mixed bag of information in the setting of biphasic activation of the JAK1-STAT3 axis that we observed here, we first examined the physical interaction between STAT3 and SMAD3 in LX-2 cells.…”

Section: Journal Of Biological Chemistry 4305mentioning

confidence: 99%

Transforming Growth Factor-β (TGF-β) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic Fibrosis in Coordination with the SMAD Pathway

Tang

Heller

Meng

et al. 2017

Journal of Biological Chemistry

222

195

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Edited by Xiao-Fan WangTransforming growth factor-␤ (TGF-␤) signals through both SMAD and non-SMAD pathways to elicit a wide array of biological effects. Existing data have shown the association and coordination between STATs and SMADs in mediating TGF-␤ functions in hepatic cells, but it is not clear how STATs are activated under these circumstances. Here, we report that JAK1 is a constitutive TGF␤RI binding protein and is absolutely required for phosphorylation of STATs in a SMAD-independent manner within minutes of TGF-␤ stimulation. Following the activation of SMADs, TGF-␤ also induces a second phase of STAT phosphorylation that requires SMADs, de novo protein synthesis, and contribution from JAK1. Our global gene expression profiling indicates that the non-SMAD JAK1/STAT pathway is essential for the expression of a subset of TGF-␤ target genes in hepatic stellate cells, and the cooperation between the JAK1-STAT3 and SMAD pathways is critical to the roles of TGF-␤ in liver fibrosis.

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“…HIES is characterized by recurrent skin abscesses, eczema, pneumonia, high levels of serum IgE, and reduced Th17 differentiation. Nonimmunological manifestations of HIES include a characteristic face, pathologic dentition, scoliosis, bone alterations (fractures with minor trauma), hyperextensible joints, and vascular abnormalities . The disease can be transmitted as an autosomal dominant trait , with full penetrance and variable expressivity .…”

Section: Introductionmentioning

confidence: 99%

Somatic mosaicism in B cells of a patient with autosomal dominant hyper IgE syndrome

et al. 2016

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Hyper IgE syndrome (HIES) is characterized by recurrent skin abscesses, eczema, pneumonia, and high levels of serum IgE. Nonimmunologic manifestations of HIES include a characteristic face, pathologic dentition, scoliosis, bone alterations, hyperextensible joints, and vascular abnormalities. Somatic mosaicism is defined by the presence of two or more populations of cells with different genotypes in one individual. In this report, we describe one patient with classical HIES and another patient with a mild phenotype, both harboring the same genetic mutation. The patient with a mild phenotype did not present the characteristic face, had normal production of IL-17A by T CD4 cells, but had low phosphorylation of STAT-3 in B cells. Interestingly, the mutation found in B cells was absent in other cell types analyzed, in agreement with the presence of a somatic mosaic genotype. The clinical and functional differences observed between these patients justify the use of complementary tools for a better definition of the cases. These approaches allow for a better understanding of complex phenotypes associated with somatic mosaicisms, and present the possibility to analyze the role of B lymphocytes in the pathophysiology of this disease. This knowledge has an impact on not only the treatment but also the provision of appropriate genetic counseling.

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Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation

Cited by 94 publications

References 60 publications

Functions of Smad Transcription Factors in TGF-β1–Induced Selectin Ligand Expression on Murine CD4 Th Cells

Functions of Smad Transcription Factors in TGF-β1–Induced Selectin Ligand Expression on Murine CD4 Th Cells

Transforming Growth Factor-β (TGF-β) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic Fibrosis in Coordination with the SMAD Pathway

Somatic mosaicism in B cells of a patient with autosomal dominant hyper IgE syndrome

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