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Pathway crosstalk enables cells to interpret TGF-? duration.

ABSTRACT: The detection and transmission of the temporal quality of intracellular and extracellular signals is an essential cellular mechanism. It remains largely unexplored how cells interpret the duration information of a stimulus. In this paper, we performed an integrated quantitative and computational analysis on TGF-? induced activation of SNAIL1, a key transcription factor that regulates several subsequent cell fate decisions such as apoptosis and epithelial-to-mesenchymal transition. We demonstrate that crosstalk among multiple TGF-? activated pathways forms a relay from SMAD to GLI1 that initializes and maintains SNAILl expression, respectively. SNAIL1 functions as a key integrator of information from TGF-? signaling distributed through upstream divergent pathways. The intertwined network serves as a temporal checkpoint, so that cells can generate a transient or sustained expression of SNAIL1 depending on TGF-? duration. Furthermore, we observed that TGF-? treatment leads to an unexpected accumulation of GSK3 molecules in an enzymatically active tyrosine phosphorylation form in Golgi apparatus and ER, followed by accumulation of GSK3 molecules in an enzymatically inhibitive serine phosphorylation in the nucleus. Subsequent model analysis and inhibition experiments revealed that the initial localized increase of GSK3 enzymatic activity couples to the positive feedback loop of the substrate Gli1 to form a network motif with multi-objective functions. That is, the motif is robust against stochastic fluctuations, and has a narrow distribution of response time that is insensitive to initial conditions. Specifically for TGF-? signaling, the motif ensures a smooth relay from SMAD to GLI1 on regulating SNAIL1 expression.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5972147 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Pathway crosstalk enables cells to interpret TGF-β duration.

Zhang Jingyu J Tian Xiao-Jun XJ Chen Yi-Jiun YJ Wang Weikang W Watkins Simon S Xing Jianhua J

NPJ systems biology and applications 20180528

The detection and transmission of the temporal quality of intracellular and extracellular signals is an essential cellular mechanism. It remains largely unexplored how cells interpret the duration information of a stimulus. In this paper, we performed an integrated quantitative and computational analysis on TGF-β induced activation of SNAIL1, a key transcription factor that regulates several subsequent cell fate decisions such as apoptosis and epithelial-to-mesenchymal transition. We demonstrate ...[more]

PMID: 29872541

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Project description:AimsPrevious reports indicated that the Slit2-Robo signalling pathway is involved in embryonic heart development and fibrosis in other solid organs, but its function in adult cardiac fibrosis has not been investigated. Here, we investigate the role of the Slit2-Robo1 signalling pathway in cardiac fibrosis.Methods and resultsThe right atrial tissue samples were obtained from patients with valvular heart disease complicated by atrial fibrillation during heart valve surgery and from healthy heart donors. The fibrotic animal model is created by performing transverse aortic constriction (TAC) surgery. The Robo1, Slit2, TGF-?1, and collagen I expression levels in human and animal samples were evaluated by immunohistochemistry and western blot analysis. Echocardiography measured the changes in heart size and cardiac functions of animals. Angiotensin II (Ang II), Slit2-siRNA, TGF-?1-siRNA, recombinant Slit2, and recombinant TGF-?1 were transfected to cardiac fibroblasts (CFs) respectively to observe their effects on collagen I expression level. The right atrial appendage of patients with valvular heart disease complicated by atrial fibrillation found significantly up-regulated Slit2, Robo1, TGF-?1, and collagen I expression levels. TAC surgery leads to heart enlargement, cardiac fibrosis, and up-regulation of Slit2, Robo1, TGF-?1, and collagen I expression levels in animal model. Robo1 antagonist R5 and TGF-?1 antagonist SB431542 suppressed cardiac fibrosis in TAC mice. Treatment with 100 nM Ang II in CFs caused significantly increased Slit2, Robo1, Smad2/3, TGF-?1, collagen I, PI3K, and Akt expression levels. Transfecting Slit2-siRNA and TGF-?1-siRNA, respectively, into rat CFs significantly down-regulated Smad2/3 and collagen I expression, inhibiting the effects of Ang II. Recombinant Slit2 activated the TGF-?1/Smad signalling pathway in CFs and up-regulated Periostin, Robo1, and collagen I expression.ConclusionsThe Slit2-Robo1 signalling pathway interfered with the TGF-?1/Smad pathway and promoted cardiac fibrosis. Blockade of Slit2-Robo1 might be a new treatment for cardiac fibrosis.

Project description:Nrf2 and TGF-β1 both affect tumorigenesis in a dual fashion, either by preventing carcinogen induced carcinogenesis and suppressing tumor growth, respectively, or by conferring cytoprotection and invasiveness to tumor cells during malignant transformation. Given the involvement of Nrf2 and TGF-β1 in the adaptation of epithelial cells to persistent inflammatory stress, e.g. of the pancreatic duct epithelium during chronic pancreatitis, a crosstalk between Nrf2 and TGF-β1 can be envisaged. By using premalignant human pancreatic duct cells (HPDE) and the pancreatic ductal adenocarcinoma cell line Colo357, we could show that Nrf2 and TGF-β1 independently but additively conferred an invasive phenotype to HPDE cells, whereas acting synergistically in Colo357 cells. This was accompanied by differential regulation of EMT markers like vimentin, Slug, L1CAM and E-cadherin. Nrf2 activation suppressed E-cadherin expression through an as yet unidentified ARE related site in the E-cadherin promoter, attenuated TGF-β1 induced Smad2/3-activity and enhanced JNK-signaling. In Colo357 cells, TGF-β1 itself was capable of inducing Nrf2 whereas in HPDE cells TGF-β1 per-se did not affect Nrf2 activity, but enhanced Nrf2 induction by tBHQ. In Colo357, but not in HPDE cells, the effects of TGF-β1 on invasion were sensitive to Nrf2 knock-down. In both cell lines, E-cadherin re-expression inhibited the proinvasive effect of Nrf2. Thus, the increased invasion of both cell lines relates to the Nrf2-dependent downregulation of E-cadherin expression. In line, immunohistochemistry analysis of human pancreatic intraepithelial neoplasias in pancreatic tissues from chronic pancreatitis patients revealed strong Nrf2 activity already in premalignant epithelial duct cells, accompanied by partial loss of E-cadherin expression. Our findings indicate that Nrf2 and TGF-β1 both contribute to malignant transformation through distinct EMT related mechanisms accounting for an invasive phenotype. Provided a crosstalk between both pathways, Nrf2 and TGF-β1 mutually promote their tumorigenic potential, a condition manifesting already at an early stage during inflammation induced carcinogenesis of the pancreas.

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Pathway crosstalk enables cells to interpret TGF-? duration.

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Pathway crosstalk enables cells to interpret TGF-β duration.

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