Role of the TAK1-NLK-STAT3 pathway in TGF-beta-mediated mesoderm induction.
Ontology highlight
ABSTRACT:
SUBMITTER: Ohkawara B
PROVIDER: S-EPMC359392 | biostudies-other | 2004 Feb
REPOSITORIES: biostudies-other
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Project description:Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine that signals through the interaction of type I (TbetaRI) and type II (TbetaRII) receptors to activate distinct intracellular pathways. TAK1 is a serine/threonine kinase that is rapidly activated by TGF-beta1. However, the molecular mechanism of TAK1 activation is incompletely understood. Here, we propose a mechanism whereby TAK1 is activated by TGF-beta1 in primary mouse mesangial cells. Under unstimulated conditions, endogenous TAK1 is stably associated with TbetaRI. TGF-beta1 stimulation causes rapid dissociation from the receptor and induces TAK1 phosphorylation. Deletion mutant analysis indicates that the juxtamembrane region including the GS domain of TbetaRI is crucial for its interaction with TAK1. Both TbetaRI-mediated TAK1 phosphorylation and TGF-beta1-induced TAK1 phosphorylation do not require kinase activity of TbetaRI. Moreover, TbetaRI-mediated TAK1 phosphorylation correlates with the degree of its association with TbetaRI and requires kinase activity of TAK1. TAB1 does not interact with TGF-beta receptors, but TAB1 is indispensable for TGF-beta1-induced TAK1 activation. We also show that TRAF6 and TAB2 are required for the interaction of TAK1 with TbetaRI and TGF-beta1-induced TAK1 activation in mouse mesangial cells. Taken together, our data indicate that TGF-beta1-induced interaction of TbetaRI and TbetaRII triggers dissociation of TAK1 from TbetaRI, and subsequently TAK1 is phosphorylated through TAB1-mediated autophosphorylation and not by the receptor kinase activity of TbetaRI.
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Project description:Nonimmunological connective tissue phenotypes in humans are common among some congenital and acquired allergic diseases. Several of these congenital disorders have been associated with either increased TGF-β activity or impaired STAT3 activation, suggesting that these pathways might intersect and that their disruption may contribute to atopy. In this study, we show that STAT3 negatively regulates TGF-β signaling via ERBB2-interacting protein (ERBIN), a SMAD anchor for receptor activation and SMAD2/3 binding protein. Individuals with dominant-negative STAT3 mutations (STAT3mut ) or a loss-of-function mutation in ERBB2IP (ERBB2IPmut ) have evidence of deregulated TGF-β signaling with increased regulatory T cells and total FOXP3 expression. These naturally occurring mutations, recapitulated in vitro, impair STAT3-ERBIN-SMAD2/3 complex formation and fail to constrain nuclear pSMAD2/3 in response to TGF-β. In turn, cell-intrinsic deregulation of TGF-β signaling is associated with increased functional IL-4Rα expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4Rα/GATA3 axis in vitro. These findings link increased TGF-β pathway activation in ERBB2IPmut and STAT3mut patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE.
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Project description:Transforming growth factor-β (TGF-β) is major inducer of epithelial-to-mesenchymal transition (EMT), which associates with cancer cell metastasis and resistance to chemotherapy and targeted drugs, through both transcriptional and non-transcriptional mechanisms. We previously reported that, in cancer cells, heightened mitogenic signaling allows TGF-β-activated Smad3 to interact with poly(RC) binding protein 1 (PCBP1) and together they regulate many alternative splicing events that favors expression of protein isoforms essential for EMT, cytoskeletal rearrangement, and adherens junction signaling. Here we show that the exclusion of TGF-β-activated kinase 1 (TAK1) variable exon 12 requires another RNA-binding protein, Fox-1 homolog 2 (Rbfox2), which binds intronic sequences in front of exon 12 independently of the Smad3-PCBP1 complex. Functionally, exon 12-excluded TAK1∆E12 and full-length TAK1FL are distinct. The short isoform TAK1∆E12 is constitutively active and supports TGF-β-induced EMT and nuclear factor kappa B (NF-κB) signaling, whereas the full-length isoform TAK1FL promotes TGF-β-induced apoptosis. These observations offer a harmonious explanation for how a single TAK1 kinase can mediate the opposing responses of cell survival and apoptosis in response to TGF-β. They also reveal a propensity of the alternatively spliced TAK1 isoform TAK1∆E12 to cause drug resistance due to its activity in supporting EMT and NF-κB survival signaling.
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Project description:BackgroundThe polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder with pathological mechanisms remain unclear. The following study investigates the ovarian hyperfibrosis forming via transforming growth factor-β (TGF-β) signaling pathway in Dehydroepiandrosterone (DHEA)- induced polycystic ovary syndrome (PCOS) rat model. We furthermore explored whether TGF-βRI inhibitor (SB431542) decreases ovarian fibrosis by counterbalancing the expression of fibrotic biomarkers.MethodsThirty female Sprague-Dawley rats were randomly divided into Blank group (n = 6), Oil group (n = 6), and Oil + DHEA-induced model group (n = 6 + 12). The model groups were established by subcutaneous injection of DHEA for 35 consecutive days. The 12 successful model rats were additionally divided in vehicle group (n = 6) and SB431542-treated group (n = 6). Vehicle group and SB431542-treated group, served as administration group and were intraperitoneally injected with DMSO and SB431542 for additional 14 consecutive days. Ovarian morphology, fibrin and collagen localization and expression in ovaries were detected using H&E staining, immunohistochemistry and Sirius red staining. The ovarian protein and RNA were examined using Western blot and RT-PCR.ResultsIn DHEA-induced ovary in rat, fibrin and collagen had significantly higher levels, while the main fibrosis markers (TGF-β, CTGF, fibronectin, a-SMA) were obviously upregulated. SB431542 significantly reduced the expression of pro-fibrotic molecules (TGF-β, Smad3, Smad2, a-SMA) and increased anti-fibrotic factor MMP2.ConclusionTGF-βRI inhibitor (SB431542) inhibits the downstream signaling molecules of TGF-β and upregulates MMP2, which in turn prevent collagen deposition. Moreover, ovarian hyperfibrosis in DHEA-induced PCOS rat model could be improved by TGF-βRI inhibitor (SB431542) restraining the transcription of accelerating fibrosis genes and modulating EMT mediator.
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Project description:WNT-5A, a key player in embryonic development and post-natal homeostasis, has been associated with a myriad of pathological conditions including malignant, fibroproliferative and inflammatory disorders. Previously, we have identified WNT-5A as a transcriptional target of TGF-β in airway smooth muscle cells and demonstrated its function as a mediator of airway remodeling. Here, we investigated the molecular mechanisms underlying TGF-β-induced WNT-5A expression. We show that TGF-β-activated kinase 1 (TAK1) is a critical mediator of WNT-5A expression as its pharmacological inhibition or siRNA-mediated silencing reduced TGF-β induction of WNT-5A. Furthermore, we show that TAK1 engages p38 and c-Jun N-terminal kinase (JNK) signaling which redundantly participates in WNT-5A induction as only simultaneous, but not individual, inhibition of p38 and JNK suppressed TGF-β-induced WNT-5A expression. Remarkably, we demonstrate a central role of β-catenin in TGF-β-induced WNT-5A expression. Regulated by TAK1, β-catenin is required for WNT-5A induction as its silencing repressed WNT-5A expression whereas a constitutively active mutant augmented basal WNT-5A abundance. Furthermore, we identify Sp1 as the transcription factor for WNT-5A and demonstrate its interaction with β-catenin. We discover that Sp1 is recruited to the WNT-5A promoter in a TGF-β-induced and TAK1-regulated manner. Collectively, our findings describe a TAK1-dependent, β-catenin- and Sp1-mediated signaling cascade activated downstream of TGF-β which regulates WNT-5A induction.
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Project description:Transforming growth factor-beta (TGF-?) has a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-? signaling enhances de novo tumor development, whereas TGF-? overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-?-induced growth arrest response is attenuated, in association with aberrant activation of nuclear factor-?B (NF-?B), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-? and NF-?B pathways plays in altered activation of these pathways has not been established. Here, we show TGF-? receptor II and TGF-?-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of NF-?B family member RELA (p65). Further, TGF-?1 treatment induced sequential phosphorylation of TAK1, IKK, I?B? and RELA in human HNSCC lines. TAK1 enhances TGF-?-induced NF-?B activation, as TAK1 siRNA knockdown decreased TGF-?1-induced phosphorylation of IKK, I?B and RELA, degradation of I?B?, RELA nuclear translocation and DNA binding, and NF-?B-induced reporter and target gene transcription. Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion. Celastrol, a TAK1 inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased TGF-?1-induced phosphorylation of TAK1 and RELA, and suppressed basal, TGF-?1- and tumor necrosis factor-alpha (TNF-?)-induced NF-?B reporter gene activity. Celastrol also inhibited cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, TGF-? and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-?-induced SMAD and NF-?B reporters when compared with constitutive or TNF-?-induced NF-?B reporter gene activation. Thus, cross-talk by TGF-? via TAK1 and NF-?B promotes the malignant phenotype of HNSCC. Moreover, NF-?B may contribute to the downstream attenuation of canonical TGF-? signaling through increased SMAD7 expression. Celastrol highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-?-NF-?B signal pathway.
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