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Signal Transduction
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Signal Transduction

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 January 2013) | Viewed by 126502

Special Issue Editor

Prof. Dr. Felix H. Brembeck

E-Mail Website
Guest Editor
Tumor Biology and Signal Transduction, Department of Hematology and Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany

Special Issue Information

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

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

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Published Papers (9 papers)

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Research

Jump to: Review

323 KiB  
Article
Adenosine Triphosphate (ATP) Is a Candidate Signaling Molecule in the Mitochondria-to-Nucleus Retrograde Response Pathway
by Feng Zhang, Tammy Pracheil, Janet Thornton and Zhengchang Liu
Genes 2013, 4(1), 86-100; https://doi.org/10.3390/genes4010086 - 20 Mar 2013
Cited by 43 | Viewed by 10565
Abstract
Intracellular communication from the mitochondria to the nucleus is achieved via the retrograde response. In budding yeast, the retrograde response, also known as the RTG pathway, is regulated positively by Rtg1, Rtg2, Rtg3 and Grr1 and negatively by Mks1, Lst8 and two 14-3-3 [...] Read more.
Intracellular communication from the mitochondria to the nucleus is achieved via the retrograde response. In budding yeast, the retrograde response, also known as the RTG pathway, is regulated positively by Rtg1, Rtg2, Rtg3 and Grr1 and negatively by Mks1, Lst8 and two 14-3-3 proteins, Bmh1/2. Activation of retrograde signaling leads to activation of Rtg1/3, two basic helix-loop-helix leucine zipper transcription factors. Rtg1/3 activation requires Rtg2, a cytoplasmic protein with an N-terminal adenosine triphosphate (ATP) binding domain belonging to the actin/Hsp70/sugar kinase superfamily. The critical regulatory step of the retrograde response is the interaction between Rtg2 and Mks1. Rtg2 binds to and inactivates Mks1, allowing for activation of Rtg1/3 and the RTG pathway. When the pathway is inactive, Mks1 has dissociated from Rtg2 and bound to Bmh1/2, preventing activation of Rtg1/3. What signals association or disassociation of Mks1 and Rtg2 is unknown. Here, we show that ATP at physiological concentrations dissociates Mks1 from Rtg2 in a highly cooperative fashion. We report that ATP-mediated dissociation of Mks1 from Rtg2 is conserved in two other fungal species, K. lactis and K. waltii. Activation of Rtg1/3 upregulates expression of genes encoding enzymes catalyzing the first three reactions of the Krebs cycle, which is coupled to ATP synthesis through oxidative phosphorylation. Therefore, we propose that the retrograde response is an ATP homeostasis pathway coupling ATP production with ATP-mediated repression of the retrograde response by releasing Mks1 from Rtg2. Full article
(This article belongs to the Special Issue Signal Transduction)
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198 KiB  
Article
Gene Expressions for Signal Transduction under Acidic Conditions
by Toshihiko Fukamachi, Syunsuke Ikeda, Xin Wang, Hiromi Saito, Masatoshi Tagawa and Hiroshi Kobayashi
Genes 2013, 4(1), 65-85; https://doi.org/10.3390/genes4010065 - 8 Mar 2013
Cited by 10 | Viewed by 6883
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 cellular signal transduction, gene expression, and cellular functions under acidic conditions. Our group showed that different signal proteins [...] Read more.
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 cellular 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 a typical medium of around pH 7.4 that has been used until now. Investigations of gene expression under acidic conditions may be crucial to our understanding of signal transduction in acidic diseased areas. In this study, we investigated gene expression in mesothelioma cells cultured at an acidic pH using a DNA microarray technique. After 24 h culture at pH 6.7, expressions of 379 genes were increased more than twofold compared with those in cells cultured at pH 7.5. Genes encoding receptors, signal proteins including transcription factors, and cytokines including growth factors numbered 35, 32, and 17 among the 379 genes, respectively. Since the functions of 78 genes are unknown, it can be argued that cells may have other genes for signaling under acidic conditions. The expressions of 37 of the 379 genes were observed to increase after as little as 2 h. After 24 h culture at pH 6.7, expressions of 412 genes were repressed more than twofold compared with those in cells cultured at pH 7.5, and the 412 genes contained 35, 76, and 7 genes encoding receptors, signal proteins including transcription factors, and cytokines including growth factors, respectively. These results suggest that the signal pathways in acidic diseased areas are different, at least in part, from those examined with cells cultured at a pH of around 7.4. Full article
(This article belongs to the Special Issue Signal Transduction)
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347 KiB  
Article
Differential Effects of MicroRNAs on Glioblastoma Growth and Migration
by Duane Jeansonne, Marco Pacifici, Adam Lassak, Krzysztof Reiss, Giuseppe Russo, Jovanny Zabaleta and Francesca Peruzzi
Genes 2013, 4(1), 46-64; https://doi.org/10.3390/genes4010046 - 4 Mar 2013
Cited by 19 | Viewed by 7540
Abstract
Glioblastoma multiforme is characterized by rapid proliferation, aggressive metastatic potential, and resistance to radio- and chemotherapy. The matricellular protein CYR61 regulates cellular proliferation and migration and is highly expressed in Glioblastomas. MicroRNAs are 22-nucleotides long RNAs that regulate gene expression post-transcriptionally. Here, we [...] Read more.
Glioblastoma multiforme is characterized by rapid proliferation, aggressive metastatic potential, and resistance to radio- and chemotherapy. The matricellular protein CYR61 regulates cellular proliferation and migration and is highly expressed in Glioblastomas. MicroRNAs are 22-nucleotides long RNAs that regulate gene expression post-transcriptionally. Here, we utilized the LN229 glioblastoma cell line and found that CYR61 is a target of miR-136, miR-155, and miR-634. Over-expression of miR-136 and miR-634 miRNAs negatively affected proliferation, but not migration, while expression of miR-155 reduced migration but did not affect the proliferation of LN229 cells. Investigation of the molecular mechanisms affected by expression of miR-634 revealed an increased phosphorylation of p70S6 kinase, suggesting an induction of the mammalian target of rapamycin (mTOR) complex 1 pathway. Additionally, in miR-634 overexpressing cells, TSC2, a negative regulator of mTOR signaling, was found to be decreased. Altogether, our study provides insights on the differential roles of miRs-136, -155, and -634 in regulating glioblastoma cell growth and migration, and how microRNAs could be manipulated to decrease the aggressiveness and metastatic potential of tumor cells. Full article
(This article belongs to the Special Issue Signal Transduction)
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Review

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250 KiB  
Review
Roles of EphA2 in Development and Disease
by Jeong Eun Park, Alexander I. Son and Renping Zhou
Genes 2013, 4(3), 334-357; https://doi.org/10.3390/genes4030334 - 1 Jul 2013
Cited by 58 | Viewed by 9643
Abstract
The Eph family of receptor tyrosine kinases (RTKs) has been implicated in the regulation of many aspects of mammalian development. Recent analyses have revealed that the EphA2 receptor is a key modulator for a wide variety of cellular functions. This review focuses on [...] Read more.
The Eph family of receptor tyrosine kinases (RTKs) has been implicated in the regulation of many aspects of mammalian development. Recent analyses have revealed that the EphA2 receptor is a key modulator for a wide variety of cellular functions. This review focuses on the roles of EphA2 in both development and disease. Full article
(This article belongs to the Special Issue Signal Transduction)
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860 KiB  
Review
Signaling Pathways from the Endoplasmic Reticulum and Their Roles in Disease
by Hisae Kadowaki and Hideki Nishitoh
Genes 2013, 4(3), 306-333; https://doi.org/10.3390/genes4030306 - 1 Jul 2013
Cited by 142 | Viewed by 21327
Abstract
The endoplasmic reticulum (ER) is an organelle in which newly synthesized secretory and transmembrane proteins are assembled and folded into their correct tertiary structures. However, many of these ER proteins are misfolded as a result of various stimuli and gene mutations. The accumulation [...] Read more.
The endoplasmic reticulum (ER) is an organelle in which newly synthesized secretory and transmembrane proteins are assembled and folded into their correct tertiary structures. However, many of these ER proteins are misfolded as a result of various stimuli and gene mutations. The accumulation of misfolded proteins disrupts the function of the ER and induces ER stress. Eukaryotic cells possess a highly conserved signaling pathway, termed the unfolded protein response (UPR), to adapt and respond to ER stress conditions, thereby promoting cell survival. However, in the case of prolonged ER stress or UPR malfunction, apoptosis signaling is activated. Dysfunction of the UPR causes numerous conformational diseases, including neurodegenerative disease, metabolic disease, inflammatory disease, diabetes mellitus, cancer, and cardiovascular disease. Thus, ER stress-induced signaling pathways may serve as 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, as well as the possible roles of ER stress in several diseases. Full article
(This article belongs to the Special Issue Signal Transduction)
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748 KiB  
Review
Non-Neuronal Functions of the M2 Muscarinic Acetylcholine Receptor
by Wymke Ockenga, Sina Kühne, Simone Bocksberger, Antje Banning and Ritva Tikkanen
Genes 2013, 4(2), 171-197; https://doi.org/10.3390/genes4020171 - 2 Apr 2013
Cited by 22 | Viewed by 28326
Abstract
Acetylcholine is an important neurotransmitter whose effects are mediated by two classes of receptors. The nicotinic acetylcholine receptors are ion channels, whereas the muscarinic receptors belong to the large family of G protein coupled seven transmembrane helix receptors. Beyond its function in neuronal [...] Read more.
Acetylcholine is an important neurotransmitter whose effects are mediated by two classes of receptors. The nicotinic acetylcholine receptors are ion channels, whereas the muscarinic receptors belong to the large family of G protein coupled seven transmembrane helix receptors. Beyond its function in neuronal systems, 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 summarize the non-neuronal functions of the muscarinic acetylcholine receptors, especially those of the M2 muscarinic receptor in epithelial cells. We will review the mechanisms of signaling by the M2 receptor but also the cellular trafficking and ARF6 mediated endocytosis of this receptor, which play an important role in the regulation of signaling events. In addition, we provide an overview of the M2 receptor in human pathological conditions such as autoimmune diseases and cancer. Full article
(This article belongs to the Special Issue Signal Transduction)
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287 KiB  
Review
Signaling Pathways in Exosomes Biogenesis, Secretion and Fate
by Lorena Urbanelli, Alessandro Magini, Sandra Buratta, Alessandro Brozzi, Krizia Sagini, Alice Polchi, Brunella Tancini and Carla Emiliani
Genes 2013, 4(2), 152-170; https://doi.org/10.3390/genes4020152 - 28 Mar 2013
Cited by 311 | Viewed by 19707
Abstract
Exosomes are small extracellular vesicles (30–100 nm) derived from the endosomal system, which have raised considerable interest in the last decade. Several studies have shown that they mediate cell-to-cell communication in a variety of biological processes. Thus, in addition to cell-to-cell direct interaction [...] Read more.
Exosomes are small extracellular vesicles (30–100 nm) derived from the endosomal system, which have raised considerable interest in the last decade. Several studies have shown that they mediate cell-to-cell communication in a variety of biological processes. Thus, in addition to cell-to-cell direct interaction or secretion of active molecules, they are now considered another class of signal mediators. Exosomes can be secreted by several cell types and retrieved in many body fluids, such as blood, urine, saliva and cerebrospinal fluid. In addition to proteins and lipids, they also contain nucleic acids, namely mRNA and miRNA. These features have prompted extensive research to exploit them as a source of biomarkers for several pathologies, such as cancer and neurodegenerative disorders. In this context, exosomes also appear attractive as gene delivery vehicles. Furthermore, exosome immunomodulatory and regenerative properties are also encouraging their application for further therapeutic purposes. Nevertheless, several issues remain to be addressed: exosome biogenesis and secretion mechanisms have not been clearly understood, and physiological functions, as well as pathological roles, are far from being satisfactorily elucidated. Full article
(This article belongs to the Special Issue Signal Transduction)
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609 KiB  
Review
The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinases (MAPKAPKs) in Inflammation
by Ugo Moens, Sergiy Kostenko and Baldur Sveinbjørnsson
Genes 2013, 4(2), 101-133; https://doi.org/10.3390/genes4020101 - 26 Mar 2013
Cited by 175 | Viewed by 14977
Abstract
Mitogen-activated protein kinase (MAPK) pathways are implicated in several cellular processes including proliferation, differentiation, apoptosis, cell survival, cell motility, metabolism, stress response and inflammation. MAPK pathways transmit and convert a plethora of extracellular signals by three consecutive phosphorylation events involving a MAPK kinase [...] Read more.
Mitogen-activated protein kinase (MAPK) pathways are implicated in several cellular processes including proliferation, differentiation, apoptosis, cell survival, cell motility, metabolism, stress response 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. In turn MAPKs phosphorylate substrates, including other protein kinases referred to as MAPK-activated protein kinases (MAPKAPKs). Eleven mammalian MAPKAPKs have been identified: ribosomal-S6-kinases (RSK1-4), mitogen- and stress-activated kinases (MSK1-2), MAPK-interacting kinases (MNK1-2), MAPKAPK-2 (MK2), MAPKAPK-3 (MK3), and MAPKAPK-5 (MK5). The role of these MAPKAPKs in inflammation will be reviewed. Full article
(This article belongs to the Special Issue Signal Transduction)
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598 KiB  
Review
Matricellular Signal Transduction Involving Calmodulin in the Social Amoebozoan Dictyostelium
by Danton H. O'Day and Robert J. Huber
Genes 2013, 4(1), 33-45; https://doi.org/10.3390/genes4010033 - 15 Feb 2013
Viewed by 6483
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 ECM proteins is the [...] Read more.
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 ECM proteins is the cysteine-rich, EGF-like (EGFL) repeat-containing, calmodulin (CaM)-binding protein (CaMBP) CyrA. The first EGFL repeat of CyrA increases the rate of random cell motility and cyclic AMP-mediated chemotaxis. Processing of full-length CyrA (~63 kDa) releases two major EGFL repeat-containing fragments (~45 kDa and ~40 kDa) in an event that is developmentally regulated. Evidence for an EGFL repeat receptor also exists and downstream intracellular signaling pathways involving 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 CaMBP in this eukaryotic microbe. In keeping with this, extracellular CaM (extCaM) has been shown to be present in the ECM sheath where it binds to CyrA and inhibits its cleavage to release the 45 kDa and 40 kDa EGFL repeat-containing fragments. The presence of extCaM and its role in regulating a matricellular protein during morphogenesis extends our understanding of CaM-mediated signal transduction in eukaryotes. Full article
(This article belongs to the Special Issue Signal Transduction)
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