Special Issue "Signal Transduction"

Guest Editor
Prof. Dr. Felix H. Brembeck
Tumor Biology and Signal Transduction, Department of Hematology and Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany
Website: http://www.uni-goettingen.de/en/96203.html
E-Mail: brembeck@med.uni-goettingen.de
Phone: +49 551 3912881 (ext.10568)
Fax: +49 551 3912534

Dear Colleagues,

Intracellular signaling is mediated by few highly conserved pathways which mediate elemental processes during embryonic development and in tissue homeostasis. Mutations of signal components within these transduction pathways are implicated in human disease such as cancer. Therefore the precise analysis of signal components and their interactions between different pathways has emerged as a challenging issue to understand tissue morphogenesis, regeneration and disease onset. Many functions have been elucidated from work in Drosophila, Xenopus and zebra fish and were re-evaluated for higher vertebrates during embryogenesis and in disease models. 
This Special Issue of “Genes” welcomes reviews and original papers covering recent research on signal transduction to provide a link between different model organisms and their specific functions for signal transduction. Special interest will be given to reports on intracellular signaling using in vitro and in vivo models for development, stem cell control or disease.

Prof. Dr. Felix H. Brembeck
Guest Editor

Submission

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• signal transduction
• development
• tissue homeostasis
• regeneration
• tumorigenesis
• embryonic stem cells
• cancer stem cells
• animal models

Type of Paper: Article
Title: Matricellular Signal Transduction Involving Calmodulin in the Social Amoebozoan Dictyostelium
Authors: Danton H. O’Day ¹ and Robert J. Huber ²
Affiliations: ¹ Department of Biology, University of Toronto Mississauga, 3359 Mississauga Road North, Mississauga, ON, Canada L5L 1C6 and Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON, Canada M5S 3G5; E-Mail: danton.oday@utoronto.ca
² Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Richard B. Simches Research Center, Boston, Massachusetts, USA 02114; E-Mail: rhuber@chgr.mgh.harvard.edu
Abstract: The social amoebozoan Dictyostelium discoideum undergoes a developmental sequence wherein an extracellular matrix (ECM) sheath surrounds a group of differentiating cells. This sheath is comprised of proteins and carbohydrates, like the ECM of mammalian tissues. One of the characterized proteins is the cysteine-rich, EGF-like (EGFL) repeat-containing protein CyrA. The first EGFL repeat of CyrA increases the rate of random cell motility and cyclic AMP-mediated chemotaxis. Processing of full-length CyrA (~65kDa) releases two major EGFL repeat-containing fragments (~45kDa and ~40kDa) an event that is developmentally regulated. Evidence for an EGFL receptor also exists and downstream intracellular signalling pathways involving calmodulin (CaM), Ras, protein kinase A and vinculin B phosphorylation have been characterized. In total, these results identify CyrA as a true matricellular protein comparable in function to tenascin C and other matricellular proteins from mammalian cells. Insight into the regulation and processing of CyrA has also been revealed. CyrA is the first identified extracellular CaM-binding protein in this eukaryotic microbe. In keeping with this, extracellular CaM has been shown to be present in the ECM sheath where it binds to CyrA and inhibits its cleavage to release the 45kDa and 40kDa EGFL repeat-containing fragments. The presence of extracellular CaM and its role in regulating a matricellular protein during morphogenesis extends our understanding of CaM-mediated signal transduction in eukaryotes.

Type of Paper: Review
Title: The Signaling Pathways from the Endoplasmic Reticulum and Diseases
Authors: Hisae Kadowaki and Hideki Nishitoh
Affiliation: Division of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan; E-Mails: kadowaki@med.miyazaki-u.ac.jp (H.K.); nishitoh@med.miyazaki-u.ac.jp (H.N.)
Abstracts: The endoplasmic reticulum (ER) is the organelle in which newly synthesized secretory and transmembrane proteins form their proper tertiary structure. However, many of these ER proteins are misfolded by various stimuli and gene mutations. The accumulation of misfolded proteins disturbs the function of the ER and induces ER stress. Eukaryotic cells possess highly conserved signaling pathway termed the unfolded protein response (UPR) to adapt to ER stress conditions and thereby survive. However, In the case of prolonged ER stress or UPR malfunction, apoptosis signaling is activated. Dysfunction of the UPR causes numerous diseases including neurodegenerative disease, metabolic disease, inflammatory disease and diabetes mellitus. ER stress signaling pathway can be potent therapeutic targets of ER stress-related diseases. In this review, we will discuss the molecular mechanisms of the UPR and ER stress-induced apoptosis and the possible roles of ER stress in several diseases.

Type of Paper: Article
Title: Gene expressions for signal transduction under acidic conditions
Authors: Toshihiko Fukamachi ¹, Syunsuke Ikeda ¹, Xin Wang ¹, Hiromi Saito ¹, Masatoshi Tagawa 2 and Hiroshi Kobayashi ¹

Affiliations: ¹ Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8675, Japan; E-Mail: hiroshi.k@mx6.ttcn.ne.jp
² Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan
Abstract: Although it is now well known that some diseased areas, such as cancer nests, inflammation loci, and infarction areas, are acidified, little is known about signal transduction, gene expression, and cellular functions under acidic conditions. Our group showed that different signal proteins were activated under acidic conditions compared with those observed in medium of pH around 7.4 used generally until now. Therefore, the investigation of gene expression under acidic conditions may be indispensable for our understanding about signal transduction in acidic diseased areas. In this study, we investigated gene expression in mesothelioma cells cultured at acidic pH using a DNA microarray technique. After 24 h culture at pH 6.7, expressions of 379 genes were increased over 2-fold compared with those in cells cultured at pH 7.5, and genes encoding receptors, signal proteins, and cytokines including growth factors were 23, 11, and 17 in the 379 genes, respectively. Since functions of 67 genes are unknown, it can be argued that cells have other genes for signaling under acidic conditions. The expressions of 39 genes in the 379 genes were observed to increase already after 2 h. These results suggest that signal pathways in acidic diseased areas are different, at least in parts, from those examined with cells cultured at pH around 7.4.

Type of Paper: Review
Title: The role of mitogen-activated protein kinase activated protein kinases (MAPKAPKs) in inflammation
Authors: Ugo Moens, Sergiy Kostenko and Baldur Sveinbjørnsson
Affiliations: Faculty of Health Sciences, Department of Medical Biology, University of Tromsø, NO-9037 Tromsø, Norway; E-Mails: ugo.moens@uit.no (U.M.); Sergiy.kostenko@uit.no (S.K.); baldur.sveinbjornsson@uit.no (B.S.)
Abstract: Mitogen-activated protein kinase (MAPK) pathways are implicated in several cellular processes including proliferation, differentiation, apoptosis, cell survival, cell motility, metabolism, and inflammation. MAPK pathways transmit and convert a plethora of extracellular signals by three consecutive phosphorylation events involving a MAPK kinase kinase, a MAPK kinase, and a MAPK. MAPKs in turn phosphorylate substrates, including other protein kinases referred to as MAPK-activated protein kinases (MAPKAPKs). Eleven mammalian MAPKAPKs have been identified: RSK1-4, MSK1-2, MNK1-2, MK2, MK3, and MK5. The role of these MAPKAPKs in inflammation will be reviewed.

Type of Paper: Review
Title: Non-neuronal Functions of the Muscarinic Acetylcholine Receptor 2
Authors: Wymke Ockenga, Sina Kuehne, Simone Bocksberger, Antje Banning and Ritva Tikkanen
Affiliation: Institute of Biochemistry, Medical Faculty, University of Giessen, Germany; E-Mail: Ritva.Tikkanen@biochemie.med.uni-giessen.de
Abstract: Acetylcholine is an important neurotransmitter whose effects are mediated by two classes of receptors. The nicotinergic receptors are ion channels, whereas the muscarinic acetylcholine receptors belong to the large family of G-protein coupled seven-transmembrane receptors. Beyond its function in neuronal system, it has become evident that acetylcholine also plays an important role in non-neuronal cells such as epithelial and immune cells. Furthermore, many cell types in the periphery are capable of synthesizing acetylcholine and express at least some of the receptors. In this review, we will focus on summarizing the non-neuronal functions of the muscarinic acetylcholine receptors, especially those of muscarinic receptor 2 (M2R) in epithelial cells. We will review the mechanisms of signaling by M2R but also the cellular trafficking and endocytosis of this receptor, which play an important role in the regulation of signaling events. In addition, we provide an overview of the M2R in human pathological conditions such as cancer.