Auswahl der wissenschaftlichen Literatur zum Thema „Membrane-Bound TGF-Β“

The type III transforming growth factor β (TGF-β) receptor (TβRIII), also known as betaglycan, is the most abundantly expressed TGF-β receptor. TβRIII suppresses breast cancer progression by inhibiting migration, invasion, metastasis, and angiogenesis. TβRIII binds TGF-β ligands, with membrane-bound TβRIII presenting ligand to enhance TGF-β signaling. However, TβRIII can also undergo ectodomain shedding, releasing soluble TβRIII, which binds and sequesters ligand to inhibit downstream signaling. To investigate the relative contributions of soluble and membrane-bound TβRIII on TGF-β signaling and breast cancer biology, we defined TβRIII mutants with impaired (ΔShed-TβRIII) or enhanced ectodomain shedding (SS-TβRIII). Inhibiting ectodomain shedding of TβRIII increased TGF-β responsiveness and abrogated TβRIII's ability to inhibit breast cancer cell migration and invasion. Conversely, expressing SS-TβRIII, which increased soluble TβRIII production, decreased TGF-β signaling and increased TβRIII-mediated inhibition of breast cancer cell migration and invasion. Of importance, SS-TβRIII–mediated increases in soluble TβRIII production also reduced breast cancer metastasis in vivo. Taken together, these studies suggest that the ratio of soluble TβRIII to membrane-bound TβRIII is an important determinant for regulation of TβRIII- and TGF-β–mediated signaling and biology.

Abstract Lactoferrin (LF) is multifunctional in the immune response. We have previously demonstrated that LF acts like TGF-β in IgA B cell differentiation. Therein, we explored whether LF affects peripheral regulatory T cell (Treg) differentiation. Indeed, LF induced Foxp3+ Treg differentiation by itself and in combination with TGF-β1 synergized to express Foxp3. It was conceivable that LF may increase Foxp3 expression through secretion of active TGF-β or facilitating latent TGF-β to active form. There was little active TGF-β in the supernatant from LF-stimulated T cells. Surprisingly, however, pan anti-TGFβ Ab completely abolished the LF-induced Foxp3 expression, suggesting that membrane-bound TGF-β may be involved. In this, we found that both LF and TGF-β1 increase latency-associated peptide negative (LAP−)TGF-β on the surface of Foxp3+T cells, and this increase was more dramatic when treated with LF plus TGF-β1. As was the case in B cells, LF-induced Foxp3 expression was virtually disappeared by pretreatment with soluble TβRIII. Collectively, these results suggest that LF induces Foxp3+Treg through TβRIII and subsequent expression of membrane-bound/LAP-negative TGF-β.

TGF-β (transforming growth factor-β) is a pleiotropic cytokine regulating diverse cellular processes. It signals through membrane-bound receptors, downstream Smad proteins and/or other signalling mediators. Smad7 has been well established to be a key negative regulator of TGF-β signalling. It antagonizes TGF-β signalling through multiple mechanisms in the cytoplasm and in the nucleus. Smad7 can be transcriptionally induced by TGF-β and other growth factors and serves as an important cross-talk mediator of the TGF-β signalling pathway with other signalling pathways. Accordingly, it plays pivotal roles in embryonic development and adult homoeostasis, and altered expression of Smad7 is often associated with human diseases, such as cancer, tissue fibrosis and inflammatory diseases.

Betaglycan and endoglin, membrane-bound co-receptors of the TGF-β family, are required to mediate the signaling of a select subset of TGF-β family ligands, TGF-β2 and InhA, and BMP-9 and BMP-10, respectively. Previous biochemical and biophysical methods suggested alternative modes of ligand binding might be responsible for these co-receptors to selectively recognize and potentiate the functions of their ligands, yet the molecular details were lacking. Recent progress determining structures of betaglycan and endoglin, both alone and as bound to their cognate ligands, is presented herein. The structures reveal relatively minor, but very significant structural differences that lead to entirely different modes of ligand binding. The different modes of binding nonetheless share certain commonalities, such as multivalency, which imparts the co-receptors with very high affinity for their cognate ligands, but at the same time provides a mechanism for release by stepwise binding of the signaling receptors, both of which are essential for their functions. Impact statement The TGF-β family is one of the most highly diversified signaling families, with essential roles in nearly all aspects of metazoan biology. Though functionally diverse, all 33 human TGF-β family ligands signal through a much more limited number of receptors. Thus the signaling repertoire is limited and cannot account for the functional diversity of signaling ligands in vivo. This mini review covers recent advances in our understanding of the structural basis by which two co-receptors of the family, betaglycan and endoglin, selectively recognize a limited subset of TGF-β family ligands and enable their functions in the cells and tissues in which they are expressed. The advances described also highlight gaps in current understanding of how the co-receptors are displaced upon engagement by the signaling receptors and how they function in a physiological environment, and thus suggest new avenues for investigation that will further illuminate how these essential co-receptors function in vivo.

There is considerable interest in delineating the molecular mechanisms of action of transforming growth factor-β (TGF-β), considered as central player in a plethora of human conditions, including cancer, fibrosis and autoimmune disease. TGF-β elicits its biological effects through membrane bound serine/threonine kinase receptors which transmit their signals via downstream signalling molecules, SMADs, which regulate the transcription of target genes in collaboration with various co-activators and co-repressors. Until now, therapeutic strategy for primary Sjögren’s syndrome (pSS) has been focused on inflammation, but, recently, the involvement of TGF-β/SMADs signalling has been demonstrated in pSS salivary glands (SGs) as mediator of the epithelial-mesenchymal transition (EMT) activation. Although EMT seems to cause pSS SG fibrosis, TGF-β family members have ambiguous effects on the function of pSS SGs. Based on these premises, this review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-β in pSS that are dictated by orchestrations of SMADs, and describe TGF-β/SMADs value as both disease markers and/or therapeutic target for pSS.

BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) is a transmembrane pseudoreceptor structurally related to transforming growth factor (TGF)-β type 1 receptors (TGF-β1Rs). BAMBI lacks a kinase domain and functions as a TGF-β1R antagonist. Essential processes such as cell differentiation and proliferation are regulated by TGF-β1R signaling. TGF-β is the best-studied ligand of TGF-βRs and has an eminent role in inflammation and fibrogenesis. Liver fibrosis is the end stage of almost all chronic liver diseases, such as non-alcoholic fatty liver disease, and at the moment, there is no effective anti-fibrotic therapy available. Hepatic BAMBI is downregulated in rodent models of liver injury and in the fibrotic liver of patients, suggesting that low BAMBI has a role in liver fibrosis. Experimental evidence convincingly demonstrated that BAMBI overexpression is able to protect against liver fibrosis. Chronic liver diseases have a high risk of hepatocellular carcinoma (HCC), and BAMBI was shown to exert tumor-promoting as well as tumor-protective functions. This review article aims to summarize relevant studies on hepatic BAMBI expression and its role in chronic liver diseases and HCC.

Endoglin is a 180-kDa glycoprotein receptor primarily expressed by the vascular endothelium and involved in cardiovascular disease and cancer. Heterozygous mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1, a vascular disease that presents with nasal and gastrointestinal bleeding, skin and mucosa telangiectases, and arteriovenous malformations in internal organs. A circulating form of endoglin (alias soluble endoglin, sEng), proteolytically released from the membrane-bound protein, has been observed in several inflammation-related pathological conditions and appears to contribute to endothelial dysfunction and cancer development through unknown mechanisms. Membrane-bound endoglin is an auxiliary component of the TGF-β receptor complex and the extracellular region of endoglin has been shown to interact with types I and II TGF-β receptors, as well as with BMP9 and BMP10 ligands, both members of the TGF-β family. To search for novel protein interactors, we screened a microarray containing over 9000 unique human proteins using recombinant sEng as bait. We find that sEng binds with high affinity, at least, to 22 new proteins. Among these, we validated the interaction of endoglin with galectin-3, a secreted member of the lectin family with capacity to bind membrane glycoproteins, and with tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase. Using human endothelial cells and Chinese hamster ovary cells, we showed that endoglin co-immunoprecipitates and co-localizes with galectin-3 or TRIM21. These results open new research avenues on endoglin function and regulation.

Abstract 17β-Estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen, mediate numerous effects in the brain, including neurosecretion, neuroprotection, and the induction of synaptic plasticity. Astrocytes, the most abundant cell type in the brain, influence many of these same functions and thus may represent a mediator of estrogen action. The present study examined the regulatory effect and underlying cell signaling mechanisms of E2-induced release of neurotropic growth factors from primary rat cortical astrocyte cultures. The results revealed that E2 (0.5, 1, and 10 nm) and tamoxifen (1 μm) increased both the expression and release of the neuroprotective cytokines, TGF-β1 and TGF-β2 (TGF-β), from cortical astrocytes. The stimulatory effect of E2 was attenuated by the estrogen receptor (ER) antagonist, ICI182,780, suggesting ER dependency. The effect of E2 also appeared to involve mediation by the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway, because E2 rapidly induced Akt phosphorylation, and pharmacological or molecular inhibition of the PI3K/Akt pathway prevented E2-induced release of TGF-β. Additionally, the membrane-impermeant conjugate, E2-BSA, stimulated the release of TGF-β, suggesting the potential involvement of a membrane-bound ER. Finally, E2, tamoxifen, and E2-BSA were shown to protect neuronal-astrocyte cocultures from camptothecin-induced neuronal cell death, effects that were attenuated by ICI182,780, Akt inhibition, or TGF-β immunoneutralization. As a whole, these studies suggest that E2 induction of TGF-β release from cortical astrocytes could provide a mechanism of neuroprotection, and that E2 stimulation of TGF-β expression and release from astrocytes occurs via an ER-dependent mechanism involving mediation by the PI3K/Akt signaling pathway.

In endothelial cells, two type I receptors of the transforming growth factor β (TGF-β) family, ALK1 and ALK5, coordinate to regulate embryonic angiogenesis in response to BMP9/10 and TGF-β. Whereas TGF-β binds to and activates ALK5, leading to Smad2/3 phosphorylation and inhibition of endothelial cell proliferation and migration, BMP9/10 and TGF-β also bind to ALK1, resulting in the activation of Smad1/5. SnoN is a negative regulator of ALK5 signaling through the binding and repression of Smad2/3. Here we uncover a positive role of SnoN in enhancing Smad1/5 activation in endothelial cells to promote angiogenesis. Upon ligand binding, SnoN directly bound to ALK1 on the plasma membrane and facilitated the interaction between ALK1 and Smad1/5, enhancing Smad1/5 phosphorylation. Disruption of this SnoN–Smad interaction impaired Smad1/5 activation and up-regulated Smad2/3 activity. This resulted in defective angiogenesis and arteriovenous malformations, leading to embryonic lethality at E12.5. Thus, SnoN is essential for TGF-β/BMP9-dependent biological processes by its ability to both positively and negatively modulate the activities of Smad-dependent pathways.

Le micro-environnement tumoral est fortement influencé par les cellules myéloïdes, dont les macrophages, les neutrophiles et les monocytes sont des représentants majeurs. Les recherches des dernières décennies ont montré que presque toutes les tumeurs sont infiltrées par des cellules myéloïdes, rendant impossible l'existence de tumeurs "froides" en ce qui concerne ces cellules. De plus, les résultats de nombreuses études cliniques se focalisant sur le compartiment immunitaire myéloïde montrent clairement que ces cellules sont presque universellement associées avec un pronostique clinique négatif chez les patients, motivant une meilleure compréhension de leur biologie et les efforts pour les cibler. Cependant, une question centrale a longtemps été de comprendre ce qui détermine les fonctions de ces cellules dans le cancer Au cours de la myélopoïèse d’urgence, l’activation pathologique des progéniteurs myéloïdes donne naissance aux cellules suppressives dérivées des myéloïdes (MDSC), une appellation rassemblant un ensemble de cellules immatures ayant une propriété commune : l’immunosuppression. En effet, les MDSC jouent un rôle crucial dans la régulation des réponses immunitaires antitumorale mais favorisent également la progression tumorale par des mécanismes non immunologiques, tels que l'influence sur l'angiogenèse et la matrice extracellulaire, la résistance aux thérapies et la préparation de la niche pré-métastatique. La préparation de la niche pré-métastatique est un élément essentiel à l’apparition de métastases à distance de la tumeur primaire, la cause principale de décès liés au cancer. Ces métastases sont initiées par une sous-population de cellules tumorales ayant des propriétés souches : les cellules souches cancéreuses (CSC). Ces cellules, aussi appelées cellules initiatrices de tumeurs (TIC), constituent une sous-population mineur au sein de la tumeur et se caractérisent par des propriétés intrinsèques distinctes telles que leur potentiel d’auto-renouvellement, la division asymétrique et leur capacité à induire une nouvelle tumeur hétérogène. D’une grande plasticité, les CSC transitionnent d’un état cellulaire à l’autre au travers de la transition épithélio-mésenchymateuse (EMT) ou son homologue, la transition mésenchymale-épithéliale (MET). De ce fait, une meilleure compréhension et des stratégies de traitements spécifiques aux CSC pourraient transformer la prise en charge clinique et améliorer significativement les taux de survie des patients. La complexité du micro-environnement tumoral, reflétée par la présence de nombreux acteurs et de leurs interactions, exerce une forte pression sélective sur les cellules cancéreuses et fournit un environnement propice à la croissance des CSC. De plus, l’implication clinique associée aux problématiques des MDSC et des CSC dirige l’émergence d’études sur leurs interactions réciproques, mais les limitations de détection de ces deux acteurs rendent l’évaluation et la compréhension des mécanismes d’interaction diffuses et incomplètes. Au cours de cette thèse, nous avons étudié le rôle des cellules myéloïdes suppressives dans l’induction de cellules cancéreuses aux propriétés souches. Nous avons montré que des cellules myéloïdes suppressives dérivées de monocyte (HuMoSC) générées in vitro, ainsi que leurs équivalents isolés de souris porteuses de tumeurs et de patients favorisaient l’apparition de CSC. Nos résultats ont mis en évidence une induction médiée par un contact direct et impliquant la forme membranaire du TGF-β. Enfin, l’étude transcriptomique des cellules myéloïdes et des cellules cancéreuses nous a également permis d’identifier une sous-population de cellules myéloïdes, exprimant la glycoprotéine CD52, comme responsable du phénomène immunosuppressif et de la plasticité des CSC vers un phénotype mésenchymateux
The tumor microenvironment is strongly influenced by myeloid cells, with macrophages, neutrophils, and monocytes being major representatives. Research over the past decades has shown that almost all tumors are infiltrated in myeloid cells, making it impossible for “cold” tumors to exist with respect to these cells. Moreover, results from numerous clinical studies focusing on the myeloid immune compartment clearly show that these cells are almost universally associated with poor clinical outcome in patients, motivating a better understanding of their biology and efforts to target them. However, a central question has long been to understand what determines the functions of these cells in cancer.During emergency myelopoiesis, pathological activation of myeloid progenitors gives rise to myeloid-derived suppressor cells (MDSC), a term that encompasses a group of immature cells with a common property: immunosuppression. Indeed, MDSC play a crucial role in regulating antitumor immune responses but also promote tumor progression through non-immunological mechanisms, such as influencing angiogenesis and the extracellular matrix, resistance to therapies, and the preparation of the pre-metastatic niche.The preparation of the pre-metastatic niche is essential for the emergence of metastases at distant sites from the primary tumor, the leading cause of cancer-related deaths. These metastases are initiated by a subpopulation of tumor cells with stem-like properties: cancer stem cells (CSC). These cells, also known as Tumor-Initiating cells (TIC), encompass a minor subpopulation within the tumor and are characterized by intrinsic properties such as self-renewal potential, asymmetric division, and the ability to induce a new, heterogeneous tumor. Highly plastic, CSC transition from one cellules state to another through the epithelial-to-mesenchymal transition (EMT) or its counterpart, the mesenchymal-to-epithelial transition (MET). Therefore, a better understanding and specific treatment strategies targeting CSC could transform clinical management and significantly improve patient survival rates.The complexity of the tumor microenvironment, reflected by the presence of numerous actors and their interactions, exerts strong selective pressure on cancer cells and provides a favorable environment for the growth of CSC. Furthermore, the clinical implications associated with the issues of MDSC and CSC drive the emergence of studies on their reciprocal interactions, but the limitations in detecting these two actors make the evaluation and understanding of their interaction mechanisms diffuse and incomplete.In this thesis, we studied the role of suppressive myeloid cells in the induction of cancer cells with stemness properties. We have shown Human Monocyte Derived Suppressive Cells (HuMoSC) generated in vitro, but also their murine and patient derived equivalent promoted the apparition of CSC. Our results have highlighted a stemness induction mediated through a direct cell-to-cell contact and involving membrane-bound TGF-β. Finally, transcriptomic study of myeloid and cancer cells allowed us to identify a subpopulation of myeloid cells, expressing the glycoprotein CD52, as responsible for the immunosuppressive properties and the plasticity of CSC towards a mesenchymal-like phenotype