TGF-β2 induces Grb2 to recruit PI3-K to TGF-RII that activates JNK/AP-1-signaling and augments invasiveness of Theileria-transformed macrophages.
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ABSTRACT:
SUBMITTER: Haidar M
PROVIDER: S-EPMC4625156 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:Theileria parasites invade and transform bovine leukocytes causing either East Coast fever (T. parva), or tropical theileriosis (T. annulata). Susceptible animals usually die within weeks of infection, but indigenous infected cattle show markedly reduced pathology, suggesting that host genetic factors may cause disease susceptibility. Attenuated live vaccines are widely used to control tropical theileriosis and attenuation is associated with reduced invasiveness of infected macrophages in vitro. Disease pathogenesis is therefore linked to aggressive invasiveness, rather than uncontrolled proliferation of Theileria-infected leukocytes. We show that the invasive potential of Theileria-transformed leukocytes involves TGF-b signalling. Attenuated live vaccine lines express reduced TGF-b2 and their invasiveness can be rescued with exogenous TGF-b. Importantly, infected macrophages from disease susceptible Holstein-Friesian (HF) cows express more TGF-b2 and traverse Matrigel with great efficiency compared to those from disease-resistant Sahiwal cattle. Thus, TGF-b2 levels correlate with disease susceptibility. Using fluorescence and time-lapse video microscopy we show that Theileria-infected, disease-susceptible HF macrophages exhibit increased actin dynamics in their lamellipodia and podosomal adhesion structures and develop more membrane blebs. TGF-b2-associated invasiveness in HF macrophages has a transcription-independent element that relies on cytoskeleton remodelling via activation of Rho kinase (ROCK). We propose that a TGF-b autocrine loop confers an amoeboid-like motility on Theileria-infected leukocytes, which combines with MMP-dependent motility to drive invasiveness and virulence.
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Project description:Activator protein (AP)-1 transcription factors are essential elements of the pro-oncogenic functions of transforming growth factor-? (TGF?)-SMAD signaling. Here we show that in multiple HER2+ and/or EGFR+ breast cancer cell lines these AP-1-dependent tumorigenic properties of TGF? critically rely on epidermal growth factor receptor (EGFR) activation and expression of the ?N isoform of transcriptional regulator p63. EGFR and ?Np63 enabled and/or potentiated the activation of a subset of TGF?-inducible invasion/migration-associated genes, e.g., ITGA2, LAMB3, and WNT7A/B, and enhanced the recruitment of SMAD2/3 to these genes. The TGF?- and EGF-induced binding of SMAD2/3 and JUNB to these gene loci was accompanied by p63-SMAD2/3 and p63-JUNB complex formation. p63 and EGFR were also found to strongly potentiate TGF? induction of AP-1 proteins and, in particular, FOS family members. Ectopic overexpression of FOS could counteract the decrease in TGF?-induced gene activation after p63 depletion. p63 is also involved in the transcriptional regulation of heparin binding (HB)-EGF and EGFR genes, thereby establishing a self-amplification loop that facilitates and empowers the pro-invasive functions of TGF?. These cooperative pro-oncogenic functions of EGFR, AP-1, p63, and TGF? were efficiently inhibited by clinically relevant chemical inhibitors. Our findings may, therefore, be of importance for therapy of patients with breast cancers with an activated EGFR-RAS-RAF pathway.
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Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) exhibit anti-neoplastic (chemoprevention) activity for sporadic cancers and the hereditary cancer predisposition Lynch syndrome (LS/HNPCC). However, the mechanism of NSAID tumor suppression has remained enigmatic. Defects in the core mismatch repair (MMR) genes MSH2 and MLH1 are the principal drivers of LS/HNPCC. Previous work has demonstrated that the villin-Cre+/-Msh2flox/flox (VpC-Msh2) mouse is a reliable model for LS/HNPCC intestinal tumorigenesis, which is significantly suppressed by treatment with the NSAID aspirin (ASA) similar to human chemoprevention. Here we show that including a TGF? receptor type-II (Tgf?-RII) mutation in the VpC-Msh2 mouse (villin-Cre+/-Msh2flox/floxTgf?-RIIflox/flox ) completely eliminates NSAID tumor suppression. These results provide strong genetic evidence that TGF? signaling and/or effectors participate in NSAID-dependent anti-neoplastic processes and provide fresh avenues for understanding NSAID chemoprevention and resistance.
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Project description:TGF-β1 is a major player in chronic liver diseases promoting fibrogenesis and tumorigenesis through various mechanisms. The expression and function of TGF-β2 have not been investigated thoroughly in liver disease to date. In this paper, we provide evidence that TGF-β2 expression correlates with fibrogenesis and liver cancer development.Using quantitative realtime PCR and ELISA, we show that TGF-β2 mRNA expression and secretion increased in murine HSCs and hepatocytes over time in culture and were found in the human-derived HSC cell line LX-2. TGF-β2 stimulation of the LX-2 cells led to upregulation of the TGF-β receptors 1, 2, and 3, whereas TGF-β1 treatment did not alter or decrease their expression. In liver regeneration and fibrosis upon CCl4 challenge, the transient increase of TGF-β2 expression was accompanied by TGF-β1 and collagen expression. In bile duct ligation-induced fibrosis, TGF-β2 upregulation correlated with fibrotic markers and was more prominent than TGF-β1 expression. Accordingly, MDR2-KO mice showed significant TGF-β2 upregulation within 3 to 15 months but minor TGF-β1 expression changes. In 5 of 8 hepatocellular carcinoma (HCC)/hepatoblastoma cell lines, relatively high TGF-β2 expression and secretion were observed, with some cell lines even secreting more TGF-β2 than TGF-β1. TGF-β2 was also upregulated in tumors of TGFα/cMyc and DEN-treated mice. The analysis of publically available microarray data of 13 human HCC collectives revealed considerable upregulation of TGF-β2 as compared to normal liver.Our study demonstrates upregulation of TGF-β2 in liver disease and suggests TGF-β2 as a promising therapeutic target for tackling fibrosis and HCC.
| S-EPMC4991397 | biostudies-literature
Project description:Transforming growth factor (TGF)-?s are dimeric polypeptides that have vital roles in regulating cell growth and differentiation. They signal by assembling a receptor heterotetramer composed of two T?RI:T?RII heterodimers. To investigate whether the two heterodimers bind and signal autonomously, one of the TGF-? protomers was substituted to block receptor binding. The substituted dimer, TGF-?3 WD, bound the T?RII extracellular domain and recruited the T?RI with affinities indistinguishable from TGF-?3, but with one-half the stoichiometry. TGF-?3 WD was further shown to retain one-quarter to one-half the signalling activity of TGF-?3 in three established assays for TGF-? function. Single-molecule fluorescence imaging with GFP-tagged receptors demonstrated a measurable increase in the proportion of T?RI and T?RII dimers upon treatment with TGF-?3, but not with TGF-?3 WD. These results provide evidence that the two T?RI:T?RII heterodimers bind and signal in an autonomous manner. They further underscore how the TGF-?s diverged from the bone morphogenetic proteins, the ancestral ligands of the TGF-? superfamily that signal through a RI:RII:RII heterotrimer.
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Project description:The TGF? receptors signal through phosphorylation and nuclear translocation of SMAD2/3. SMAD7, a transcriptional target of TGF? signals, negatively regulates the TGF? pathway by recruiting E3 ubiquitin ligases and targeting TGF? receptors for ubiquitin-mediated degradation. In this report, we identify a deubiquitylating enzyme USP11 as an interactor of SMAD7. USP11 enhances TGF? signalling and can override the negative effects of SMAD7. USP11 interacts with and deubiquitylates the type I TGF? receptor (ALK5), resulting in enhanced TGF?-induced gene transcription. The deubiquitylase activity of USP11 is required to enhance TGF?-induced gene transcription. RNAi-mediated depletion of USP11 results in inhibition of TGF?-induced SMAD2/3 phosphorylation and TGF?-mediated transcriptional responses. Central to TGF? pathway signalling in early embryogenesis and carcinogenesis is TGF?-induced epithelial to mesenchymal transition. USP11 depletion results in inhibition of TGF?-induced epithelial to mesenchymal transition.
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Project description:BackgroundPancreatic cancer characterizes high recurrence and poor prognosis. In clinical practice, radiotherapy is widely used for pancreatic cancer treatment. However, the outcome remains undesirable due to tumor repopulation and following recurrence and metastasis after radiation. So, it is highly needed to explore the underlying molecular mechanisms and accordingly develop therapeutic strategies. Our previous studies revealed that dying cells from chemoradiation could stimulate repopulation of surviving pancreatic cancer cells. However, we still knew little how dying cells provoke pancreatic cancer cell repopulation. We herein would explore the significance of TGF-β2 changes and investigate the modulation of microRNA-193a (miR-193a), and identify their contributions to pancreatic cancer repopulation and metastasis.MethodsIn vitro and in vivo repopulation models were established to mimic the biological processes of pancreatic cancer after radiation. Western blot, real-time PCR and dual-luciferase reporter assays were accordingly used to detect miR-193a and TGF-β2/TGF-βRIII signalings at the level of molecular, cellular and experimental animal model, respectively. Flow cytometry analysis, wound healing and transwell assay, vascular endothelial cell penetration experiment, and bioluminescence imaging were employed to assessthe biological behaviors of pancreatic cancer after different treatments. Patient-derived tumor xenograft (PDX) mice models were established to evaluate the therapeutic potential of miR-193a antagonist on pancreatic cancer repopulation and metastasis after radiation.ResultsmiR-193a was highly expressed in the irradiated pancreatic cancer dying cells, accordingly elevated the level of miR-193a in surviving cells, and further promoted pancreatic cancer repopulation and metastasis in vitro and in vivo. miR-193a accelerated pancreatic cancer cell cycle and stimulated cell proliferation and repopulation through inhibiting TGF-β2/TGF-βRIII/SMADs/E2F6/c-Myc signaling, and even destroyed normal intercellular junctions and promoted metastasis via repressing TGF-β2/TGF-βRIII/ARHGEF15/ABL2 pathway. Knockdown of miR-193a or restoration of TGF-β2/TGF-βRIII signaling in pancreatic cancer cells was found to block pancreatic cancer repopulation and metastasis after radiation. In PDX models, the treatment in combination with miR-193a antagonist and radiation was found to dramatically inhibit pancreatic cancer cell repopulation and metastasis, and further improved the survival after radiation.ConclusionsOur findings demonstrated that miR-193a stimulated pancreatic cancer cell repopulation and metastasis through modulating TGF-β2/TGF-βRIII signalings, and miR-193a might be a potential therapeutic target for pancreatic cancer repopulation and metastasis.
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Project description:PurposeTo analyze the relationship between transforming growth factor-beta 2 (TGF- β 2) levels in the anterior chamber aqueous humor and axial length of patients with myopia.MethodsTGF- β 2 was measured with the Luminex xMAP Technology by using commercially available Milliplex xMAP Kits. Sixty-five aqueous humor samples were collected during cataract or clear lens extraction surgery and TGF- β 2 levels in these specimens were analyzed. According to the axial length, the samples were divided into three groups: A (AL ≤ 24 mm), B (24 ~ 29 mm), and C (AL ≥ 29 mm).ResultsAqueous humor samples were analyzed from subjects with an average age of 67.0 ± 11.7 years. Mean TGF- β 2 concentration of all aqueous samples was 422.2 ± 258.8 pg/mL. TGF- β 2 concentration in group C (543 ± 317 pg/mL) was significantly greater than that in group A (390 ± 212 pg/mL) and group B (337 ± 217 pg/mL). The concentration of TGF- β 2 was positively correlated with axial length (r = 0.308, P = 0.013).ConclusionsTGF- β 2 is likely to be acting as a critical factor in axial elongation and development of myopia.
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Project description:BACKGROUND:Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson's disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. METHODS:Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. RESULTS:We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-β2 (TGF-β2)-TGF-β type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-β2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. CONCLUSIONS:These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders.
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Project description:In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) that line joint synovial membranes aggressively invade the extracellular matrix, destroying cartilage and bone. As signal transduction in FLS is mediated through multiple pathways involving protein tyrosine phosphorylation, we sought to identify protein tyrosine phosphatases (PTPs) regulating the invasiveness of RA FLS. We describe that the transmembrane receptor PTP? (RPTP?), encoded by the transforming growth factor (TGF) ?-target gene, PTPRK, promotes RA FLS invasiveness.Gene expression was quantified by quantitative PCR. PTP knockdown was achieved using antisense oligonucleotides. FLS invasion and migration were assessed in transwell or spot assays. FLS spreading was assessed by immunofluorescence microscopy. Activation of signalling pathways was analysed by Western blotting of FLS lysates using phosphospecific antibodies. In vivo FLS invasiveness was assessed by intradermal implantation of FLS into nude mice. The RPTP? substrate was identified by pull-down assays.PTPRK expression was higher in FLS from patients with RA versus patients with osteoarthritis, resulting from increased TGFB1 expression in RA FLS. RPTP? knockdown impaired RA FLS spreading, migration, invasiveness and responsiveness to platelet-derived growth factor, tumour necrosis factor and interleukin 1 stimulation. Furthermore, RPTP? deficiency impaired the in vivo invasiveness of RA FLS. Molecular analysis revealed that RPTP? promoted RA FLS migration by dephosphorylation of the inhibitory residue Y527 of SRC.By regulating phosphorylation of SRC, RPTP? promotes the pathogenic action of RA FLS, mediating cross-activation of growth factor and inflammatory cytokine signalling by TGF? in RA FLS.
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