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Rik Derynck - One of the best experts on this subject based on the ideXlab platform.

  • TGF Beta Signaling in tumor suppression and cancer progression
    Nature Genetics, 2001
    Co-Authors: Rik Derynck, Rosemary J Akhurst, Allan Balmain
    Abstract:

    Epithelial and hematopoietic cells have a high turnover and their progenitor cells divide continuously, making them prime targets for genetic and epigenetic changes that lead to cell transformation and tumorigenesis. The consequent changes in cell behavior and responsiveness result not only from genetic alterations such as activation of oncogenes or inactivation of tumor suppressor genes, but also from altered production of, or responsiveness to, stimulatory or inhibitory growth and differentiation factors. Among these, transforming growth factor β (TGF-β) and its Signaling effectors act as key determinants of carcinoma cell behavior. The autocrine and paracrine effects of TGF-β on tumor cells and the tumor micro-environment exert both positive and negative influences on cancer development. Accordingly, the TGF-β Signaling pathway has been considered as both a tumor suppressor pathway and a promoter of tumor progression and invasion. Here we evaluate the role of TGF-β in tumor development and attempt to reconcile the positive and negative effects of TGF-β in carcinogenesis.

  • a kinase subdomain of transforming growth factor β TGF β type i receptor determines the TGF β intracellular Signaling specificity
    The EMBO Journal, 1997
    Co-Authors: Xinhua Feng, Rik Derynck
    Abstract:

    Transforming growth factor-Beta (TGF-Beta) signals through a heteromeric complex of related type I and type II serine/threonine kinase receptors. In Mv1Lu cells the type I receptor TBetaRI mediates TGF-Beta-induced gene expression and growth inhibition, while the closely related type I receptors Tsk7L and TSR1 are inactive in these responses. Using chimeras between TBetaRI and Tsk7L or TSR1, we have defined the structural requirements for TGF-Beta Signaling by TBetaRI. The extracellular/transmembrane or cytoplasmic domains of TBetaRI and Tsk7L were functionally not equivalent. The juxtamembrane domain, including the GS motif, and most regions in the kinase domain can functionally substitute for each other, but the alphaC-Beta4-Beta5 region from kinase subdomains III to V conferred a distinct Signaling ability. Replacement of this sequence in TBetaRI by the corresponding domain of Tsk7L inactivated TGF-Beta Signaling, whereas its introduction into Tsk7L conferred TGF-Beta Signaling. The differential Signaling associated with this region was narrowed down to a sequence of eight amino acids, the L45 loop, which is exposed in the three-dimensional kinase structure and diverges highly between TBetaRI and Tsk7L or TSR1. Replacement of the L45 sequence in Tsk7L with that of TBetaRI conferred TGF-Beta responsiveness to the Tsk7L cytoplasmic domain in Mv1Lu cells. Thus, the L45 sequence between kinase subdomains IV and V specifies TGF-Beta responsiveness of the type I receptor.

  • ligand independent activation of transforming growth factor TGF Beta Signaling pathways by heteromeric cytoplasmic domains of TGF Beta receptors
    Journal of Biological Chemistry, 1996
    Co-Authors: Xinhua Feng, Rik Derynck
    Abstract:

    Transforming growth factor Beta (TGF-Beta) transduces signals through two related serine/threonine kinase receptors, the type I and type II receptors, which have the ability to interact with each other. In the heteromeric complex, the type II receptor is the primary determinant of ligand binding and phosphorylates the cytoplasmic domain of the type I receptor. Using a chimeric receptor strategy, we and others have shown previously that a functional TGF-Beta receptor complex requires heteromerization of both extracellular and intracellular domains of type I and type II receptors. In the current study, we show that overexpression of two receptors carrying a heteromeric combination of cytoplasmic domains resulted in ligand-independent responses, further supporting the functional requirement of the two heterologous cytoplasmic domains in TGF-Beta Signaling. Furthermore, coexpression of only the cytoplasmic domains of both the type I and II receptors or tethering the type II to the type I cytoplasmic domain activated TGF-Beta responses in a ligand-independent manner. In cotransfected COS-1 cells, both cytoplasmic domains are associated with each other. Our results indicate that the cytoplasmic domains of the type I and type II TGF-Beta receptors physically and functionally interact with each other in the heteromeric complex.

Xinhua Feng - One of the best experts on this subject based on the ideXlab platform.

  • regulation of smad4 sumoylation and transforming growth factor Beta Signaling by protein inhibitor of activated stat1
    Journal of Biological Chemistry, 2004
    Co-Authors: Min Liang, Xinhua Feng, Frauke Melchior, Xia Lin
    Abstract:

    The tumor suppressor, Smad4/DPC4, is a common signal transducer in transforming growth factor-Beta (TGF-Beta) Signaling. In this study, we demonstrated that the protein inhibitor of activated STAT1 (PIAS1) regulates the Signaling potential of Smad4 through a sumoylation-dependent mechanism. PIAS1 was shown to be an E3 ligase for Smad4 sumoylation in vitro and in vivo. PIAS1 physically interacted with Smad4 in a TGF-Beta-inducible manner. A minimal SUMO E3 ligase domain and Smad4-binding domain were defined on PIAS1 protein. The RING finger domain of PIAS1 was essential for its E3 ligase function. Although PIAS1 enhanced the Smad4-dependent transcriptional activation of TGF-Beta Signaling, a mutant lacking the RING domain inhibited the sumoylation of Smad4 in a dominant negative manner and, as a result, abolished the transcriptional response of TGF-Beta. These data demonstrate that PIAS1 protein positively modulates TGF-Beta responses as a SUMO E3 ligase for Smad4.

  • sumo 1 ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor smad4
    Journal of Biological Chemistry, 2003
    Co-Authors: Xia Lin, Min Liang, Yaoyun Liang, Charles F Brunicardi, Xinhua Feng
    Abstract:

    Tumor suppressor Smad4/DPC4 is a central intracellular signal transducer for transforming growth factor-Beta (TGF-Beta) Signaling. We recently reported that transcriptional potential of Smad4 was regulated by SUMOylation in transfected HeLa cells (1), but the precise mechanism and function of Smad4 SUMOylation in TGF-Beta Signaling remain to be elucidated. Here, we describe the regulation of TGF-Beta Signaling by SUMOylation through the control of Smad4 metabolic stability and subcellular localization. We found that SUMO-1 overexpression strongly increases Smad4 levels, while inhibition of SUMOylation by small interfering RNA (siRNA)-mediated knockdown of the E2 enzyme Ubc9 reduces endogenous Smad4 levels. Concomitantly, SUMO-1 overexpression enhances and Ubc9 knockdown reduces levels of intranuclear Smad4, growth inhibitory response, as well as transcriptional responses to TGF-Beta. Comparison of wild type and mutant forms of Smad4 for SUMOylation, ubiquitination, and half-life allows the conclusion that SUMO-1 modification serves to protect Smad4 from ubiquitin-dependent degradation and consequently enhances the growth inhibitory and transcriptional responses of Smad4.

  • a kinase subdomain of transforming growth factor β TGF β type i receptor determines the TGF β intracellular Signaling specificity
    The EMBO Journal, 1997
    Co-Authors: Xinhua Feng, Rik Derynck
    Abstract:

    Transforming growth factor-Beta (TGF-Beta) signals through a heteromeric complex of related type I and type II serine/threonine kinase receptors. In Mv1Lu cells the type I receptor TBetaRI mediates TGF-Beta-induced gene expression and growth inhibition, while the closely related type I receptors Tsk7L and TSR1 are inactive in these responses. Using chimeras between TBetaRI and Tsk7L or TSR1, we have defined the structural requirements for TGF-Beta Signaling by TBetaRI. The extracellular/transmembrane or cytoplasmic domains of TBetaRI and Tsk7L were functionally not equivalent. The juxtamembrane domain, including the GS motif, and most regions in the kinase domain can functionally substitute for each other, but the alphaC-Beta4-Beta5 region from kinase subdomains III to V conferred a distinct Signaling ability. Replacement of this sequence in TBetaRI by the corresponding domain of Tsk7L inactivated TGF-Beta Signaling, whereas its introduction into Tsk7L conferred TGF-Beta Signaling. The differential Signaling associated with this region was narrowed down to a sequence of eight amino acids, the L45 loop, which is exposed in the three-dimensional kinase structure and diverges highly between TBetaRI and Tsk7L or TSR1. Replacement of the L45 sequence in Tsk7L with that of TBetaRI conferred TGF-Beta responsiveness to the Tsk7L cytoplasmic domain in Mv1Lu cells. Thus, the L45 sequence between kinase subdomains IV and V specifies TGF-Beta responsiveness of the type I receptor.

  • ligand independent activation of transforming growth factor TGF Beta Signaling pathways by heteromeric cytoplasmic domains of TGF Beta receptors
    Journal of Biological Chemistry, 1996
    Co-Authors: Xinhua Feng, Rik Derynck
    Abstract:

    Transforming growth factor Beta (TGF-Beta) transduces signals through two related serine/threonine kinase receptors, the type I and type II receptors, which have the ability to interact with each other. In the heteromeric complex, the type II receptor is the primary determinant of ligand binding and phosphorylates the cytoplasmic domain of the type I receptor. Using a chimeric receptor strategy, we and others have shown previously that a functional TGF-Beta receptor complex requires heteromerization of both extracellular and intracellular domains of type I and type II receptors. In the current study, we show that overexpression of two receptors carrying a heteromeric combination of cytoplasmic domains resulted in ligand-independent responses, further supporting the functional requirement of the two heterologous cytoplasmic domains in TGF-Beta Signaling. Furthermore, coexpression of only the cytoplasmic domains of both the type I and II receptors or tethering the type II to the type I cytoplasmic domain activated TGF-Beta responses in a ligand-independent manner. In cotransfected COS-1 cells, both cytoplasmic domains are associated with each other. Our results indicate that the cytoplasmic domains of the type I and type II TGF-Beta receptors physically and functionally interact with each other in the heteromeric complex.

Aristidis Moustakas - One of the best experts on this subject based on the ideXlab platform.

  • Long non-coding RNAs and TGF-Beta Signaling in cancer
    Cancer Science, 2020
    Co-Authors: Panagiotis Papoutsoglou, Aristidis Moustakas
    Abstract:

    Cancer is driven by genetic mutations in oncogenes and tumor suppressor genes and by cellular events that develop a misregulated molecular microenvironment in the growing tumor tissue. The tumor microenvironment is guided by the excessive action of specific cytokines including transforming growth factor-Beta (TGF-Beta), which normally controls embryonic development and the homeostasis of young or adult tissues. As a consequence of the genetic alterations generating a given tumor, TGF-Beta can preserve its homeostatic function and attempt to limit neoplastic expansion, whereas, once the tumor has progressed to an aggressive stage, TGF-Beta can synergize with various oncogenic stimuli to facilitate tumor invasiveness and metastasis. TGF-Beta Signaling mechanisms via Smad proteins, various ubiquitin ligases, and protein kinases are relatively well understood. Such mechanisms regulate the expression of genes encoding proteins or non-coding RNAs. Among non-coding RNAs, much has been understood regarding the regulation and function of microRNAs, whereas the role of long non-coding RNAs is still emerging. This article emphasizes TGF-Beta Signaling mechanisms leading to the regulation of non-coding genes, the function of such non-coding RNAs as regulators of TGF-Beta Signaling, and the contribution of these mechanisms in specific hallmarks of cancer.

  • mechanisms of TGF Beta Signaling in regulation of cell growth and differentiation
    Immunology Letters, 2002
    Co-Authors: Aristidis Moustakas, Katerina Pardali, Annamaria Gaal, Carlhenrik Heldin
    Abstract:

    Transforming growth factor Beta (TGF-Beta) is a secreted protein that regulates proliferation, differentiation and death of various cell types. All immune cell lineages, including B, T and dendritic cells as well as macrophages, secrete TGF-Beta, which negatively regulates their proliferation, differentiation and activation by other cytokines. Thus, TGF-Beta is a potent immunosuppressor and perturbation of TGF-Beta Signaling is linked to autoimmunity, inflammation and cancer. Regulation of cell proliferation and differentiation by TGF-Beta is a topic of great basic and clinical importance. We summarize our work on the growth inhibitory pathway downstream of TGF-Beta, which is triggered by receptor serine/threonine kinases at the cell surface and downstream effectors of the Smad family. Activated Smads regulate transcription of target genes, including cell cycle inhibitors such as p21, which mediate the anti-proliferative response and partially explain the tumor suppressive action of the TGF-Beta pathway. We have described a molecular mechanism of regulation of the p21 gene by Smads and transcription factor Sp1. At late stages of tumor progression, TGF-Beta promotes tumorigenesis via suppression of the immune system and changes in cell differentiation of epithelial tumor cells, a phenomenon termed epithelial to mesenchymal transdifferentiation (EMT). We review our work on the role of the Smad pathway in controlling EMT. In conclusion, the molecular pathways that describe the anti-proliferative and transdifferentiating effects of TGF-Beta in epithelial cells have been uncovered to great molecular detail; a future challenge will be to test their generality in other systems, including the immune system.

Harold L Moses - One of the best experts on this subject based on the ideXlab platform.

  • a tale of two proteins differential roles and regulation of smad2 and smad3 in TGF Beta Signaling
    Journal of Cellular Biochemistry, 2007
    Co-Authors: Kimberly A Brown, Jennifer A Pietenpol, Harold L Moses
    Abstract:

    Transforming growth factor-Beta (TGF-Beta) is an important growth inhibitor of epithelial cells, and insensitivity to this cytokine results in uncontrolled cell proliferation and can contribute to tumorigenesis. Smad2 and Smad3 are direct mediators of TGF-Beta Signaling, however little is known about the selective activation of Smad2 versus Smad3. The Smad2 and Smad3 knockout mouse phenotypes and studies comparing Smad2 and Smad3 activation of TGF-Beta target genes, suggest that Smad2 and Smad3 have distinct roles in TGF-Beta Signaling. The observation that TGF-Beta inhibits proliferation of Smad3-null mammary gland epithelial cells, whereas Smad3 deficient fibroblasts are only partially growth inhibited, suggests that Smad3 has a different role in epithelial cells and fibroblasts. Herein, the current understanding of Smad2 and Smad3-mediated TGF-Beta Signaling and their relative roles are discussed, in addition to potential mechanisms for the selective activation of Smad2 versus Smad3. Since alterations in the TGF-Beta Signaling pathway play an important role in promoting tumorigenesis and cancer progression, methods for therapeutic targeting of the TGF-Beta Signaling pathway are being pursued. Determining how Smad2 or Smad3 differentially regulate the TGF-Beta response may translate into developing more effective strategies for cancer therapy.

  • effect of conditional knockout of the type ii TGF Beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle t antigen induced tumor formation and metastasis
    Cancer Research, 2005
    Co-Authors: Elizabeth Forrester, Mary Aakre, Brian Bierie, Alireza Sharifafshar, William J Muller, Anna Chytil, Agnieszka E Gorska, Harold L Moses
    Abstract:

    Transforming growth factor-Beta (TGF-Beta) isoforms are growth factors that function physiologically to regulate development, cellular proliferation, and immune responses. The role of TGF-Beta Signaling in mammary tumorigenesis is complex, as TGF-Beta has been reported to function as both a tumor suppressor and tumor promoter. To elucidate the role of TGF-Beta Signaling in mammary gland development, tumorigenesis, and metastasis, the gene encoding type II TGF-Beta receptor, TGFbr2, was conditionally deleted in the mammary epithelium (TGFbr2MGKO). Loss of TGFbr2 in the mammary epithelium results in lobular-alveolar hyperplasia in the developing mammary gland and increased apoptosis. TGFbr2MGKO mice were mated to the mouse mammary tumor virus-polyomavirus middle T antigen (PyVmT) transgenic mouse model of metastatic breast cancer. Loss of TGFbr2 in the context of PyVmT expression results in a shortened median tumor latency and an increased formation of pulmonary metastases. Thus, our studies support a tumor-suppressive role for epithelial TGF-Beta Signaling in mammary gland tumorigenesis and show that pulmonary metastases can occur and are even enhanced in the absence of TGF-Beta Signaling in the carcinoma cells.

  • TGF Beta Signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia
    Science, 2004
    Co-Authors: Neil A Bhowmick, Anna Chytil, David Plieth, Agnieszka E Gorska, Nancy Dumont, Scott B Shappell, Kay M Washington, Eric G Neilson, Harold L Moses
    Abstract:

    Stromal cells can have a significant impact on the carcinogenic process in adjacent epithelia. The role of transforming growth factor-Beta (TGF-Beta) Signaling in such epithelial-mesenchymal interactions was determined by conditional inactivation of the TGF-Beta type II receptor gene in mouse fibroblasts (TGFbr2fspKO). The loss of TGF-Beta responsiveness in fibroblasts resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach, both associated with an increased abundance of stromal cells. Activation of paracrine hepatocyte growth factor (HGF) Signaling was identified as one possible mechanism for stimulation of epithelial proliferation. Thus, TGF-Beta Signaling in fibroblasts modulates the growth and oncogenic potential of adjacent epithelia in selected tissues.

Anita B Roberts - One of the best experts on this subject based on the ideXlab platform.

  • transforming growth factor β receptor associated protein 1 is a smad4 chaperone
    Journal of Biological Chemistry, 2001
    Co-Authors: Jens U Wurthner, David B Frank, Angelina Felici, Harry M Green, Zhouhong Cao, M Schneider, James G Mcnally, Robert J Lechleider, Anita B Roberts
    Abstract:

    Members of the transforming growth factor-Beta (TGF-Beta) superfamily signal through unique cell membrane receptor serine-threonine kinases to activate downstream targets. TRAP1 is a previously described 96-kDa cytoplasmic protein shown to bind to TGF-Beta receptors and suggested to play a role in TGF-Beta Signaling. We now fully characterize the binding properties of TRAP1, and show that it associates strongly with inactive heteromeric TGF-Beta and activin receptor complexes and is released upon activation of Signaling. Moreover, we demonstrate that TRAP1 plays a role in the Smad-mediated signal transduction pathway, interacting with the common mediator, Smad4, in a ligand-dependent fashion. While TRAP1 has only a small stimulatory effect on TGF-Beta Signaling in functional assays, deletion constructs of TRAP1 inhibit TGF-Beta Signaling and diminish the interaction of Smad4 with Smad2. These are the first data to identify a specific molecular chaperone for Smad4, suggesting a model in which TRAP1 brings Smad4 into the vicinity of the receptor complex and facilitates its transfer to the receptor-activated Smad proteins.

  • role of transforming growth factor β Signaling in cancer
    Journal of the National Cancer Institute, 2000
    Co-Authors: Mark P De Caestecker, Ester Piek, Anita B Roberts
    Abstract:

    : Signaling from transforming growth factor-Beta (TGF-Beta) through its unique transmembrane receptor serine-threonine kinases plays a complex role in carcinogenesis, having both tumor suppressor and oncogenic activities. Tumor cells often escape from the antiproliferative effects of TGF-Beta by mutational inactivation or dysregulated expression of components in its Signaling pathway. Decreased receptor function and altered ratios of the TGF-Beta type I and type II receptors found in many tumor cells compromise the tumor suppressor activities of TGF-Beta and enable its oncogenic functions. Recent identification of a family of intracellular mediators, the Smads, has provided new paradigms for understanding mechanisms of subversion of TGF-Beta Signaling by tumor cells. In addition, several proteins recently have been identified that can modulate the Smad-Signaling pathway and may also be targets for mutation in cancer. Other pathways such as various mitogen-activated protein kinase cascades also contribute substantially to TGF-Beta Signaling. Understanding the interplay between these Signaling cascades as well as the complex patterns of cross-talk with other Signaling pathways is an important area of investigation that will ultimately contribute to understanding of the bifunctional tumor suppressor/oncogene role of TGF-Beta in carcinogenesis.