TGF-β receptor levels regulate the specificity of signaling pathway activation and biological effects of TGF-β

Clinical Research Division, Fred Hutchinson Cancer Research Center, WA 98109, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 03/2009; 1793(7):1165-73. DOI: 10.1016/j.bbamcr.2009.02.001
Source: PubMed


TGF-beta is a pluripotent cytokine that mediates its effects through a receptor composed of TGF-beta receptor type II (TGFBR2) and type I (TGFBR1). The TGF-beta receptor can regulate Smad and nonSmad signaling pathways, which then ultimately dictate TGF-beta's biological effects. We postulated that control of the level of TGFBR2 is a mechanism for regulating the specificity of TGF-beta signaling pathway activation and TGF-beta's biological effects. We used a precisely regulatable TGFBR2 expression system to assess the effects of TGFBR2 expression levels on signaling and TGF-beta mediated apoptosis. We found Smad signaling and MAPK-ERK signaling activation levels correlate directly with TGFBR2 expression levels. Furthermore, p21 levels and TGF-beta induced apoptosis appear to depend on relatively high TGFBR2 expression and on the activation of the MAPK-ERK and Smad pathways. Thus, control of TGFBR2 expression and the differential activation of TGF-beta signaling pathways appears to be a mechanism for regulating the specificity of the biological effects of TGF-beta.

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Available from: Dean Cress, Oct 09, 2014
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    • "Reduced TGFBR2 expression levels are correlated with a shorter survival rate of colon cancer patients, as does the reduced expression of the co-receptor betaglycan in breast and PC patients [8,9]. High expression levels of TGFBR2 can mediate the pro-apoptotic function of the TGFβ1 signaling pathway and its loss promotes invasion and malignant transformation [10,11]. "
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    ABSTRACT: Prostate cancer (PC) is the most frequently diagnosed cancer in men. The acquisition of castration-resistant (CR) phenotype is associated with the activation of signaling pathways mediated by growth factors. The TGFβ1 and its receptors have an important role in tumor progression, being the pro-apoptotic function modulated by the expression of TGFBR2. A single nucleotide polymorphism -875 G > A in TGFBR2 gene has been described, which may influence the expression levels of the receptor. Our purpose was to investigate the potential role of TGFBR2-875G>A in PC risk and in the response to androgen deprivation therapy (ADT). TGFBR2-875G>A polymorphism was studied by allelic discrimination using real-time polymerase chain reaction (PCR) in 891 patients with PC and 874 controls. A follow-up study was undertaken to evaluate response to ADT. The TGFBR2 and SMAD7 mRNA expression were analyzed by a quantitative real-time PCR. We found that TGFBR2-875GG homozygous patients present lower expression levels of TGFBR2 mRNA (AA/AG: 2(-ΔΔCT) =1.5, P=0.016). GG genotype was also associated with higher Gleason grade (OR=1.51, P=0.019) and increased risk of an early relapse after ADT (HR=1.47, P=0.024). The concordance (c) index analysis showed that the definition of profiles that contains information regarding tumor characteristics associated with genetic information present an increased capacity to predict the risk for CR development (c-index model 1: 0.683 vs model 2: 0.736 vs model 3: 0.746 vs model 4: 0.759). The TGFBR2-875G>A contribution to an early relapse in ADT patients, due to changes in mRNA expression, supports the involvement of TGFβ1 pathway in CRPC. Furthermore, according to our results, we hypothesize the potential benefits of the association of genetic information in predictive models of CR development.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "For example, during epithelial regeneration TGF-β antagonizes mitogenic Ras signaling, but in tumor progression TGF-β and Ras act synergistically [24]. Ras GTPases participate downstream in the signaling of TGF-β, and share some signal pathways such as PI3K/Akt and MEK/Erk 1/2 [25] [26] [27] [28] [29]. "
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    ABSTRACT: In addition to their role as oncogenes, Ras GTPases are key regulators of cell function. There is a proven relationship between the signalling pathways of transforming growth factor-β1 (TGF- β1) and Ras GTPases. Each of the Ras isoforms (H, N and K) exhibits specific modulatory activity on different cellular pathways. Our purpose has been to study some of the mechanisms involved in the development of renal fibrosis, assessing the individual role of N-Ras in basal and TGF- β1-mediated extracellular matrix (ECM) synthesis, proliferation, and migration in immortalized N-Ras deficient fibroblasts (N-ras(-/-)). Compared to normal counterparts, fibroblasts deficient for N-Ras exhibited higher basal activity levels of phosphatidylinositol-3-kinase (PI3K)/Akt and MEK/Erk, accompanied by upregulated collagen synthesis and diminished proliferation and migration rates. We found that the absence of N-Ras did not affect TGF-β1- induced proliferation and migration, which required PI3K/Akt but not Erk1/2 activation. Similar effector pathway dependence was found for fibronectin and collagen type I expression. Our results indicate that N-Ras might contribute to renal fibrosis through the down-regulation of ECM synthesis and up-regulation proliferation and migration modulating Akt activation. N-Ras also regulates TGF-β1- induced collagen I and fibronectin expression through Erk-independent pathways.
    Full-text · Article · Jul 2013 · Biochimica et Biophysica Acta
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    • "Our present study was aimed to analyze in vivo the possible HPV E5-induced alteration of the TGFβ signaling pathway in human lesions as well as its in vitro modulation under the expression of the E5 oncogenic protein. Since the local tissue concentration of the cytokine TGFβ might be extremely variable, depending on the inflammatory and immunological microenvironment [11,16], we focused both in vivo and in vitro on the expression of the receptor, since its levels are thought to strictly regulate the specificity of the TGFβ signaling and the biological activity of the cytokine [17]. In addition, because the biological behaviour of human HaCaT keratinocytes is drastically affected by TGFβ/Smad signaling [18], we took advantage of this sensitive cellular model in which 16E5 expression alone can be induced by trasfection in dose and time controlled manner. "
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    ABSTRACT: Background Infection with high-risk human papillomavirus (HR-HPV) genotypes, mainly HPV16 and HPV18, is a major risk factor for cervical cancer and responsible for its progression. While the transforming role of the HPV E6 and E7 proteins is more characterized, the molecular mechanisms of the oncogenic activity of the E5 product are still only partially understood, but appear to involve deregulation of growth factor receptor expression. Since the signaling of the transforming growth factor beta (TGFbeta) is known to play crucial roles in the epithelial carcinogenesis, aim of this study was to investigate if HPV16 E5 would modulate the TGF-BRII expression and TGFbeta/Smad signaling. Findings The HPV16 E5 mRNA expression pattern was variable in low-grade squamous intraepithelial lesions (LSIL), while homogeneously reduced in high-grade lesions (HSIL). Parallel analysis of TGFBRII mRNA showed that the receptor transcript levels were also variable in LSILs and inversely related to those of the viral protein. In vitro quantitation of the TGFBRII mRNA and protein in human keratinocytes expressing 16E5 in a dose-dependent and time-dependent manner showed a progressive down-modulation of the receptor. Phosphorylation of Smad2 and nuclear translocation of Smad4 were also decreased in E5-expressing cells stimulated with TGFbeta1. Conclusions Taken together our results indicate that HPV16 E5 expression is able to attenuate the TGFbeta1/Smad signaling and propose that this loss of signal transduction, leading to destabilization of the epithelial homeostasis at very early stages of viral infection, may represent a crucial mechanism of promotion of the HPV-mediated cervical carcinogenesis.
    Full-text · Article · May 2013 · Molecular Cancer
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