Actin-Mediated Gene Expression Depends on RhoA and Rac1 Signaling in Proximal Tubular Epithelial Cells

Morphological alterations of cells can lead to modulation of gene expression. An essential link is the MKL1-dependent activation of serum response factor ( SRF), which translates changes in the ratio of G-and F-actin into mRNA transcription. SRF activation is only partially characterized in non-transformed epithelial cells. Therefore, the impact of GTPases of the Rho family and changes in F-actin structures were analyzed in renal proximal tubular epithelial cells. Activation of SRF signaling was compared to the regulation of a known MKL1/ SRF target gene, connective tissue growth factor ( CTGF). In the human proximal tubular cell line HKC-8 overexpression of two actin mutants either favoring or preventing the formation of F-actin fibers regulated SRF-mediated transcription as well as CTGF expression. Only overexpression of constitutively active RhoA activated SRF-dependent gene expression whereas no effect was detected upon overexpression of Rac1 mutants. To elucidate the functional role of Rho kinases as downstream mediators of RhoA, pharmacological inhibition and genetic inhibition by transient siRNA knock down were compared. Upon stimulation with lysophosphatidic acid ( LPA) Rho kinase inhibitors partially suppressed SRF-mediated transcription, whereas interference with Rho kinase expression by siRNA reduced activation of SRF, but barely affected CTGF expression. Together with the partial inhibition of CTGF expression by the pharmacological inhibitors Y27432 and H1154, Rho kinases seem to be less important in mediating RhoA signaling related to CTGF expression in HKC8 epithelial cells. Short term pharmacological inhibition of Rac1 activity by EHT1864 reduced SRF-dependent CTGF expression in HKC-8 cells, but was overcome by a stimulatory effect after prolonged incubation after 4-6 h. Similarly, human primary cells of proximal but not of distal tubular origin showed inhibitory as well as stimulatory effects of Rac1 inhibition. Thus, RhoA signaling activates MKL1-SRF-mediated CTGF expression in proximal tubular cells, whereas Rac1 signaling is more complex with adaptive cellular responses

Transforming growth factor-β-induced upregulation of transforming growth factor-β receptor expression in pancreatic regeneration

AbstractThe transforming growth factor-β (TGFβ) signaling pathway is one important player in the regulation of extracellular matrix turnover and cell proliferation in epithelial regeneration. We used cerulein-induced pancreatitis in rats as a model to investigate the regulation of TGFβ receptor type I and type II expression on protein and messenger RNA level during regeneration. In the regenerating pancreas, mRNA levels of TGFβ receptor I and II were significantly increased with a maximum after 2 days. On protein level, expression of TGFβ receptor II was significantly increased after 3–5 days. This elevated expression could be inhibited by neutralizing the endogenous biological activity of TGFβ1 with a specific antibody. In cultured pancreatic epithelial cells, TGFβ1 reduced cell proliferation as measured by [3H]thymidine incorporation. Furthermore the transcript levels of TGFβ1 as well as mRNA and protein concentrations of type I and type II receptor increased during TGFβ stimulation in vitro. These results indicate that epithelial pancreatic cells contribute to the enhanced TGFβ1 synthesis during pancreatic regeneration by an autocrine mechanism. TGFβ1, furthermore, upregulates the expression of its own receptors during the regenerative process, thereby contributing to the increase of the TGFβ-induced cellular responses

Signal Transduction in the Footsteps of Goethe and Schiller

The historical town of Weimar in Thuringia, the "green heart of Germany" was the sphere of Goethe and Schiller, the two most famous representatives of German literature's classic era. Not yet entirely as influential as those two cultural icons, the Signal Transduction Society (STS) has nevertheless in the last decade established within the walls of Weimar an annual interdisciplinary Meeting on "Signal Transduction – Receptors, Mediators and Genes", which is well recognized as a most attractive opportunity to exchange results and ideas in the field

Signal transduction, receptors, mediators and genes: younger than ever - the 13th meeting of the Signal Transduction Society focused on aging and immunology

The 13th meeting of the Signal Transduction Society was held in Weimar, from October 28 to 30, 2009. Special focus of the 2009 conference was "Aging and Senescence", which was co-organized by the SFB 728 "Environmentally-Induced Aging Processes" of the University of Düsseldorf and the study group 'Signal Transduction' of the German Society for Cell Biology (DGZ). In addition, several other areas of signal transduction research were covered and supported by different consortia associated with the Signal Transduction Society including the long-term associated study groups of the German Society for Immunology and the Society for Biochemistry and Molecular Biology, and for instance the SFB/Transregio 52 "Transcriptional Programming of Individual T Cell Subsets" located in Würzburg, Mainz and Berlin. The different research areas that were introduced by outstanding keynote speakers attracted more than 250 scientists, showing the timeliness and relevance of the interdisciplinary concept and exchange of knowledge during the three days of the scientific program. This report gives an overview of the presentations of the conference

Закономерности формирования угольных бассейнов Южно-Гобийской провинции Монголии и содержание в них редких элементов

Background— Ion channels are key determinants for the function of excitable cells, but little is known about their role and involvement during cardiac development. Earlier work identified Ca 2+ -activated potassium channels of small and intermediate conductance (SKCas) as important regulators of neural stem cell fate. Here we have investigated their impact on the differentiation of pluripotent cells toward the cardiac lineage. Methods and Results— We have applied the SKCa activator 1-ethyl-2-benzimidazolinone on embryonic stem cells and identified this particular ion channel family as a new critical target involved in the generation of cardiac pacemaker-like cells: SKCa activation led to rapid remodeling of the actin cytoskeleton, inhibition of proliferation, induction of differentiation, and diminished teratoma formation. Time-restricted SKCa activation induced cardiac mesoderm and commitment to the cardiac lineage as shown by gene regulation, protein, and functional electrophysiological studies. In addition, the differentiation into cardiomyocytes was modulated in a qualitative fashion, resulting in a strong enrichment of pacemaker-like cells. This was accompanied by induction of the sino-atrial gene program and in parallel by a loss of the chamber-specific myocardium. In addition, SKCa activity induced activation of the Ras-Mek-Erk signaling cascade, a signaling pathway involved in the 1-ethyl-2-benzimidazolinone–induced effects. Conclusions— SKCa activation drives the fate of pluripotent cells toward mesoderm commitment and cardiomyocyte specification, preferentially into nodal-like cardiomyocytes. This provides a novel strategy for the enrichment of cardiomyocytes and in particular, the generation of a specific subtype of cardiomyocytes, pacemaker-like cells, without genetic modification. </jats:sec

Report of the 24th Meeting on Signal Transduction 2021

The annual meeting &ldquo;Signal Transduction&mdash;Receptors, Mediators and Genes&rdquo; of the Signal Transduction Society (STS) is an interdisciplinary conference which is open to all scientists sharing a common interest in the elucidation of the signaling pathways mediating physiological or pathological processes in the health and disease of humans, animals, plants, fungi, prokaryotes, and protists. The 24th meeting on signal transduction was held from 15 to 17 November 2021 in Weimar, Germany. As usual, keynote presentations by invited scientists introduced the respective workshops, and were followed by speakers chosen from the submitted abstracts. A special workshop focused on &ldquo;Target Identification and Interaction&rdquo;. Ample time was reserved for the discussion of the presented data during the workshops. Unfortunately, due to restrictions owing to the SARS-CoV-2 pandemic, the poster sessions&mdash;and thus intensive scientific discussions at the posters&mdash;were not possible. In this report, we provide a concise summary of the various workshops and further aspects of the scientific program

Report of the Signal Transduction Society Meeting 2017—Metabolism in Health and Disease

The annual “Joint Meeting Signal Transduction—Receptors, Mediators and Genes” of the Signal Transduction Society (STS) aims to be an interdisciplinary forum for researchers who share a common interest in deciphering signal transduction pathways in normal or transformed cells, in health and disease, in humans and animal models, or in plants or bacteria. The special focus of the 21st annual Joint Meeting, which took place from 8–10 November 2017 in Weimar, was the topic “Metabolism in Health and Disease” and covered multiple aspects of this highly exciting and fast developing research field. Invited keynote speakers introduced the impact of metabolism on tumor immunology, immune cell signaling, and posttranslational modifications in three specific workshops to the audience. Various other aspects of signal transduction were intensively discussed in five additional workshops. Here, we give an overview of the various workshops and further aspects of the scientific program

Report of the Signal Transduction Society Meeting 2018—Signaling: From Past to Future

The annual meeting &ldquo;Signal Transduction&mdash;Receptors, Mediators, and Genes&rdquo; of the Signal Transduction Society (STS) is an interdisciplinary conference open to all scientists sharing the common interest in elucidating signaling pathways in physiological or pathological processes in humans, animals, plants, fungi, prokaryotes, and protists. On the occasion of the 20th anniversary of the STS, the 22nd joint meeting took place in Weimar from 5&ndash;7 November 2018. With the focus topic &ldquo;Signaling: From Past to Future&rdquo; the evolution of the multifaceted research concerning signal transduction since foundation of the society was highlighted. Invited keynote speakers introduced the respective workshop topics and were followed by numerous speakers selected from the submitted abstracts. All presentations were lively discussed during the workshops. Here, we provide a concise summary of the various workshops and further aspects of the scientific program

Ptk7 Is Dynamically Localized at Neural Crest Cell–Cell Contact Sites and Functions in Contact Inhibition of Locomotion

Neural crest (NC) cells are highly migratory cells that contribute to various vertebrate tissues, and whose migratory behaviors resemble cancer cell migration and invasion. Information exchange via dynamic NC cell–cell contact is one mechanism by which the directionality of migrating NC cells is controlled. One transmembrane protein that is most likely involved in this process is protein tyrosine kinase 7 (PTK7), an evolutionary conserved Wnt co-receptor that is expressed in cranial NC cells and several tumor cells. In Xenopus, Ptk7 is required for NC migration. In this study, we show that the Ptk7 protein is dynamically localized at cell–cell contact zones of migrating Xenopus NC cells and required for contact inhibition of locomotion (CIL). Using deletion constructs of Ptk7, we determined that the extracellular immunoglobulin domains of Ptk7 are important for its transient accumulation and that they mediate homophilic binding. Conversely, we found that ectopic expression of Ptk7 in non-NC cells was able to prevent NC cell invasion. However, deletion of the extracellular domains of Ptk7 abolished this effect. Thus, Ptk7 is sufficient at protecting non-NC tissue from NC cell invasion, suggesting a common role of PTK7 in contact inhibition, cell invasion, and tissue integrity