The role of LTBPs in TGF beta signaling

The purpose of this review is to discuss the transforming growth factor beta (TGFB) binding proteins (LTBP) with respect to their participation in the activity of TGFB. We first describe pertinent aspects of the biology and cell function of the LTBPs. We then summarize the physiological consequences of LTBP loss in humans and mice. Finally, we consider a number of outstanding questions relating to LTBP function.     

TGF-{beta} signaling of human T cells is modulated by the ancillary TGF-{beta} receptor endoglin

Transforming growth factor beta (TGF-beta) inhibits T cell activation and alters differentiation of naive T cells into effector cells. Although four main cell-surface proteins can interact with TGF-beta, only the signaling receptors type I (TGF-betaR type I) and type II (TGF-betaR type II) have so far been described on T cells. The aim of the present study was to investigate the expression of the ancillary receptor endoglin (CD105) by T cells and its role in TGF-beta-mediated signal transduction and function. CD105 expression was analyzed on resting and activated human CD4(+) T cells by flow cytometry, western blot, immunoprecipitation, proliferation and SMAD-responsive reporter gene assays. CD4(+) T cells constitutively expressed CD105 in memory T cells and partially also in naive T cells; however, surface expression is regulated and is increased following TCR engagement, which induced serine/threonine phosphorylation of CD105. In contrast to the suppressive signal mediated by the TGF-beta, cross-linking of CD105 substantially enhanced T cell proliferation, indicating that CD105 by itself mediates signal transduction. Furthermore, CD105 cross-linking induced SMAD-independent signaling via ERK kinase phosphorylation. The present study demonstrates that CD105 is expressed on the surface by activated CD4(+) T cells and CD3 regulated by post-translational means. Furthermore, CD105 acts as a regulatory receptor, counteracting TGF-beta-mediated suppression.     

Separation of transforming growth factors TGF alpha and TGF beta during chromatographic purification of extracts from mouse C-234 tumors

Polypeptide transforming growth factors: TGF alpha and TGF beta were isolated and separated from acidic ethanol extracts of mouse C-243 tumors. The purification of the acid-soluble extract was achieved by Bio-Gel P-60 filtration chromatography, followed by CM-Sepharose CL-6B ion exchange, Bio-Gel P-10 filtration, and dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). At the Bio-Gel P-10 purification step, TGF alpha was separated from TGF beta. TGF alpha stimulated mouse Balb/c-3T3, rat NRK-49F and human A549 cells to form colonies in soft agar, and competed with 125I-labeled epidermal growth factor (EGF) for binding to human placenta membrane receptors. Over 40,000-fold SDS-PAGE-purified TGF beta had an Mr of 25,000. Unlike TGF alpha, TGF beta stimulated the clonal growth of NRK fibroblasts only in the presence of the suboptimal amounts of EGF (0.5 ng/ml). TGF beta significantly inhibited the anchorage-independent growth of malignant human lung carcinoma A549 cells, and in the radioreceptor assay with 125I-EGF it had no affinity to EGF receptors.     

T cell signaling: a decision of life and death.

T lymphocytes constitute an essential part of the immune system. Their generation, activation, proliferation but also survival is subject to tight regulation by several extracellular factors including cytokines, MHC-antigen complexes and co-stimulatory ligands. The balanced interplay between these factors determines the fate of the T cell. Both in thymic development and in a peripheral immune response, triggering of the T cell antigen receptor (TCR) through interaction with the MHC-antigen complex can result in T cell proliferation. However, in the absence of co-stimulatory signals from antigen-presenting cells a state of non-responsiveness is induced that is called anergy. In addition, stimulation of the TCR on activated T cells or thymocytes can lead to the induction of apoptosis. Here we will give an overview of the intracellular signal transduction pathways that are activated by the stimuli that dictate the fate of a T cell as they were presented at the International Symposium on soluble HLA antigens held in 1997 in Brussels.     

Control of the cell survival/death decision by cannabinoids

Cannabinoids, the active components of Cannabis sativa (marijuana), and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical application. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to cannabinoids in recent years. One of the most exciting and promising areas of current cannabinoid research is the ability of these compounds to control the cell survival/death decision. Thus cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells, including neurons, lymphocytes, and various transformed neural and nonneural cells. The variation in drug effects may depend on experimental factors such as drug concentration, timing of drug delivery, and type of cell examined. Regarding the central nervous system, most of the experimental evidence indicates that cannabinoids may protect neurons from toxic insults such as glutamaergic overstimulation, ischemia and oxidative damage. In contrast, cannabinoids induce apoptosis of glioma cells in culture and regression of malignant gliomas in vivo. Breast and prostate cancer cells are also sensitive to cannabinoid-induced antiproliferation. Regarding the immune system, low doses of cannabinoids may enhance cell proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis. The neuroprotective effect of cannabinoids may have potential clinical relevance for the treatment of neurodegenerative disorders such as multiple sclerosis, Parkinson's disease, and ischemia/stroke, whereas their growth-inhibiting action on transformed cells might be useful for the management of malignant brain tumors. Ongoing investigation is in search for cannabinoid-based therapeutic strategies devoid of nondesired psychotropic effects.     

Control of cell fate by the formation of an architecturally complex bacterial community

Bacteria form architecturally complex communities known as biofilms in which cells are held together by an extracellular matrix. Biofilms harbor multiple cell types, and it has been proposed that within biofilms individual cells follow different developmental pathways, resulting in heterogeneous populations. Here we demonstrate cellular differentiation within biofilms of the spore-forming bacterium Bacillus subtilis, and present evidence that formation of the biofilm governs differentiation. We show that motile, matrix-producing, and sporulating cells localize to distinct regions within the biofilm, and that the localization and percentage of each cell type is dynamic throughout development of the community. Importantly, mutants that do not produce extracellular matrix form unstructured biofilms that are deficient in sporulation. We propose that sporulation is a culminating feature of biofilm formation, and that spore formation is coupled to the formation of an architecturally complex community of cells.     

Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells

RBP-J is a key mediator of Notch signaling that regulates cell fate determination in various lineages. To investigate the function of Notch-RBP-J in mature B cell differentiation, we generated mice that selectively lacked B cell RBP-J expression using conditional mutagenesis. Absence of RBP-J led to the loss of marginal zone B (MZB) cells with a concomitant increase in follicular B cells; in contrast, B1 cells in the peritoneal cavity were unaffected. Lack of RBP-J caused no defects in B cells maintenance, survival, plasma cell differentiation or activation. It is therefore likely that Notch-RBP-J signaling regulates the lineage commitment of mature B cells into follicular versus MZB cells. In addition, in mice with RBP-J-deficient B cells, had no obvious changes in immunoglobulin production in response to Ficoll, lipopolysaccharide or chicken gammaglobulin. In contrast, these mice exhibited increased mortality rates after blood-borne bacterial infection, which indicates that MZB cells play pivotal roles in the clearance of these bacteria.