Next Article in Journal
Silicon Era of Carbon-Based Life: Application of Genomics and Bioinformatics in Crop Stress Research
Next Article in Special Issue
Role of Cytokine Signaling during Nervous System Development
Previous Article in Journal
Notch Signaling Pathway Is Activated in Motoneurons of Spinal Muscular Atrophy
Previous Article in Special Issue
Cellular Functions Regulated by Phosphorylation of EGFR on Tyr845

Int. J. Mol. Sci. 2013, 14(6), 11438-11443; doi:10.3390/ijms140611438

Editorial
Editorial of the Special Issue: Signaling Molecules and Signal Transduction in Cells
Jens Schlossmann
Pharmacology and Toxicology, Institute of Pharmacy, University Regensburg, Universitätsstr, 31, D-93040 Regensburg, Germany; E-Mail: jens.schlossmann@chemie.uni-regensburg.de; Tel.: +49-941-943-4770; Fax: +49-941-943-4771
Received: 3 May 2013; in revised form: 20 May 2013 / Accepted: 22 May 2013 /
Published: 29 May 2013

Abstract

: In the special issue “Signaling Molecules and Signal Transduction in Cells” authors were invited to submit papers regarding important and novel aspects of extra- and intracellular signaling which have implications on physiological and pathophysiological processes. These aspects included compounds which are involved in these processes, elucidation of signaling pathways, as well as novel techniques for the analysis of signaling pathways. In response, various novel and important topics are elucidated in this special issue.
Keywords:
signaling; signaling molecules; receptors; second messenger; kinases; phosphatases; posttranslational modifications; intercellular signaling

1. Communication

Several of the manuscripts presented discuss compounds which might be involved in cellular apoptosis and thereby influence cancer or embryonic development.

The compound Ginsenoside Rh2 (G-Rh2), derived from the plant Ginseng, acts anti-proliferative and pro-apoptotic. Its intracellular effects through apoptotic pathways were analyzed by Guo et al. Rapamycin is an inhibitor of mTOR (mammalian target of rapamycin) and thereby acts antiproliferative on some tumors [1]. Dai et al. studied the anti-tumor effect of rapamycin inducing apoptosis and autophagy on pancreatic cancer cells [2]. Sun et al. proffer that JRS-15, a derivative of xylocydine which was a novel cyclin-dependent kinase inhibitor, induced mitochondrial apoptosis in several cancer cell lines [3]. Kalimuthu et al. reviewed the effect of various bioactive compounds from marine organisms including sponges, actinomycetes and soft corals on the diverse apoptotic pathways of cancer cells [4].

The common mycotoxin ochratoxin A (OTA) is nephrotoxic, hepatotoxic and immunotoxic. The cytotoxic effects of OTA on mouse embryonic development inducing reactive oxygen species and mitochondrial apoptosis were studied by Hsuuw et al. [5]. Wnt morphogens are involved in various stages of development, including migration, cell polarity, proliferation and differentiation. Solis et al. reviewed the role of reggie/flotillin proteins for Wnt secretion and gradient formation and its effect on development [6]. Furthermore, Senarath-Yapa et al. reported the osteogenic potential of diverse signaling pathways including Wnt, BMP, FGF and TGFβ [7]. Adams et al. analyzed the toxic effect of cesium in plants. High concentrations of cesium inhibited plant growth inducing the jasmonate pathway and thereby probably modified potassium uptake machineries [8]. The differential role of defense response pathways, the unfolded protein response (UPR) and the steroid response element (SREBP) was studied by Bedoya-Perez et al. in the mosquito Aedes aegypti using the Cry11Aa toxin [9]. Further, the UPR signaling pathways in mammalian and their implications were reviewed by Carrara et al. [10].

G-Protein coupled receptors (GPCR) represent the most abundant class of mammalian membrane-bound receptors and are valuable pharmacological targets. The review by De Kejzer et al. described prostaglandin E2 GPCR signaling in dendritic cells in respect to the cellular life cycle [11]. Resolvin (resolution-phase interaction products) is a member of a novel family of aspirin-triggered short-lived autacoids synthesized during inflammation. Keinan et al. presented resolvin signaling pathways which could be used in oral health treatment [12].

Growth factors are important mediators of developmental processes. Mutations in the tyrosine kinase growth factor receptors are known to induce severe diseases, including the susceptibility to cancer. Therefore, the regulation of growth factor receptor signaling is essential for the understanding of physiology and pathophysiology of these proteins. In this regard, the link of EGFR to the intracellular dynein IC2 was described by Pullikuth et al. [13]. Furthermore, mechanisms for the spatial regulation of EGFR signaling including endocytosis were elucidated by Ceresa et al. [14]. The mechanism of EGFR phosphorylation and its link to interacting proteins in uterine myoma was analyzed by Weissenbacher et al. [15]. They found that EGFR Y845 phosphorylation probably interacted with Mucin-1 and cleaved Galectin-3 which could serve as a diagnostic tool for differentiation of benign and malign tumors. Regulation of endocytosis and cell signaling is an emerging role of intersectins which were summarized by Hunter et al. [16]. There were implications of intersectins in human diseases including Down syndrome, Alzheimer disease and cancer.

Muha et al. explained the role of fibroblast growth factor (FGF) and the FGF receptors Heartless(Htl) and Breathless (Btl) for development and differentiation in Drosophila [17]. Conidi et al. described that interference of peptide apatamers with growth factors e.g., TGFβ or EGFR could be suitable for the analysis of their signaling pathways in high throughput screening studies [18]. Formyl peptide receptor 2 agonists, their distinct signaling pathways and their involvement in immunological responses and cancer were reviewed by Cattaneo et al. [19].

Erythropoietin (EPO) induces erythropoiesis and is used as a pharmacological drug, e.g., as biosimilars for long-term treatment of anemia. However, EPO also acts on other types of cells, e.g., endothelial mediating proliferative and angiogenic effects and might be important for the therapeutic outcome. Trincavelli et al. discussed the effect of EPO, its derivatives and the serine/threonine kinase receptor EPO-R in endothelial cells, regarding desensitization/resensitization/expression using an in vitro model [20]. Hänel et al. discussed the role of cytokines in healthy and inflammatory skin diseases [21].

Functions of the retinoid nuclear orphan receptor RORα were reviewed by Du et al. implicating its role as tumor suppressor [22].

Mutations in the gene ATP2C cause the Hailey-Hailey skin disease in humans. ATP2C1 encodes the secretory pathway calcium (Ca2+)-ATPase pump (SPCA1). Micaroni et al. hypothesized that the gene ASTE1 influences ATP2C1 gene expression. ASTE1 dysregulation might induce cell death and tumor transformation [23].

Nitric oxide is an important signaling molecule which exerts pleiotropic functions. Its regulatory function in skeletal muscle during exercise was summarized by Suhr et al. [24]. Soluble guanylyl cyclases are activated by nitric oxide and thereby synthesize the second messenger cGMP. The detection of cGMP in vivo is an emerging field which was presented in comparison to cAMP by Sprenger et al. in a featured review paper [25].

Kinase cascades are essential for the intracellular signal transduction. In this regard, the MAP kinase scaffold was reviewed by Meister et al. [26] coordinating the cellular response. Candelori et al. presented a study regarding the gene En-MAPK1 which was activated during pheromone signaling of the polar ciliate Euplotes nobili [27]. Furthermore, Joshi et al. described the regulation of T-Cell activation and function by diacylglycerol kinases [28].

Phosphorylation is controlled by protein phosphatases. Recently, atypical protein phosphatases were discovered which were structurally different from the known families of Ser/Thr- and Tyr-phosphatases. Sadatomi et al. set its focus on the atypical phosphatases eyes absent (EYA) which acted as dual Thr/Tyr-phosphatase and members of the phosphoglycerate mutase (PGAM) family (Sts-1, Sts-2, PGAM5) which exerted His-based Tyr-phosphatase activity [29].

The ubiquitination of proteins is a proteasomal degradation motif. However, ubiquitination is also used as an intracellular receptor signaling motif. In this regard, the ubiquitination of Notch and its signaling intracellular function was reviewed by Moretti et al. Small GTP-binding proteins are important regulators of intracellular signaling [30]. As an example, the function of protein RhoA in the intestinal epithelial barrier was summarized by Tong et al. [31]. A further posttranslational modification includes SUMOylation, e.g., on ATF3. Its role inhibiting prostate cancer cells was presented by Wang et al. [32].

The controlled release of compounds from cells is important for intercellular signaling and communication. Beyond various exocytosis mechanisms, the analysis and implication of exosomes for (patho)physiological processes is a topic which was reviewed in detail by Corrado et al. [33]. The composition of exosomes is not fully elucidated and is variable in various differentiated cells. However, there are numerous processes described involving exosomes with implications for health and disease, e.g., for immune response, neuronal signaling, rheumatoid arthritis and various cancers. The role of prostaglandins for intercellular neuronal signaling of endothelia, astrocytes and neurons and their involvement in neuronal injury was summarized by Takemiya et al. [34].

2. Conclusions

In summary, several important and novel aspects of intracellular and intercellular signaling in health and disease were highlighted in this special issue. However, signal transduction in and from cells is a huge field which can only partly be touched on in one special issue. Therefore, a further special issue covering more aspects of this engrossing field will follow in 2014.

Acknowledgments

The work was supported by the state of Bavaria and the Deutsche Forschungsgemeinschaft DFG.

Conflict of Interest

The authors declare no conflict of interest.

References

  1. Guo, X.X.; Guo, Q.; Li, Y.; Lee, S.K.; Wei, X.N.; Jin, Y.H. Ginsenoside rh2 induces human hepatoma cell apoptosisvia bax/bak triggered cytochrome C release and caspase-9/caspase-8 activation. Int. J. Mol. Sci 2012, 13, 15523–15535. [Google Scholar]
  2. Dai, Z.J.; Gao, J.; Ma, X.B.; Kang, H.F.; Wang, B.F.; Lu, W.F.; Lin, S.; Wang, X.J.; Wu, W.Y. Antitumor effects of rapamycin in pancreatic cancer cells by inducing apoptosis and autophagy. Int. J. Mol. Sci 2013, 14, 273–285. [Google Scholar]
  3. Sun, C.; Guo, X.X.; Zhu, D.; Xiao, C.; Bai, X.; Li, Y.; Zhan, Z.; Li, X.L.; Song, Z.G.; Jin, Y.H. Apoptosis is induced in cancer cells via the mitochondrial pathway by the novel xylocydine-derived compound JRS-15. Int. J. Mol. Sci 2013, 14, 850–870. [Google Scholar]
  4. Kalimuthu, S.; Se-Kwon, K. Cell survival and apoptosis signaling as therapeutic target for cancer: Marine bioactive compounds. Int. J. Mol. Sci 2013, 14, 2334–2354. [Google Scholar]
  5. Hsuuw, Y.D.; Chan, W.H.; Yu, J.S. Ochratoxin a inhibits mouse embryonic development by activating a mitochondrion-dependent apoptotic signaling pathway. Int. J. Mol. Sci 2013, 14, 935–953. [Google Scholar]
  6. Solis, G.P.; Luchtenborg, A.M.; Katanaev, V.L. Wnt secretion and gradient formation. Int. J. Mol. Sci 2013, 14, 5130–5145. [Google Scholar]
  7. Senarath-Yapa, K.; Li, S.; Meyer, N.P.; Longaker, M.T.; Quarto, N. Integration of multiple signaling pathways determines differences in the osteogenic potential and tissue regeneration of neural crest-derived and mesoderm-derived calvarial bones. Int. J. Mol. Sci 2013, 14, 5978–5997. [Google Scholar]
  8. Adams, E.; Abdollahi, P.; Shin, R. Cesium inhibits plant growth through jasmonate signaling in Arabidopsis thaliana. Int. J. Mol. Sci 2013, 14, 4545–4559. [Google Scholar]
  9. Bedoya-Perez, L.P.; Cancino-Rodezno, A.; Flores-Escobar, B.; Soberon, M.; Bravo, A. Role of UPR Pathway in defense response of Aedes aegypti against Cry11Aa Toxin from Bacillus thuringiensis. Int. J. Mol. Sci 2013, 14, 8467–8478. [Google Scholar]
  10. Carrara, M.; Prischi, F.; Ali, M.M. UPR signal activation by luminal sensor domains. Int. J. Mol. Sci 2013, 14, 6454–6466. [Google Scholar]
  11. De Keijzer, S.; Meddens, M.B.; Torensma, R.; Cambi, A. The multiple faces of prostaglandin E2 G-protein coupled receptor signaling during the dendritic cell life cycle. Int. J. Mol. Sci 2013, 14, 6542–6555. [Google Scholar]
  12. Keinan, D.; Leigh, N.J.; Nelson, J.W.; de Oleo, L.; Baker, O.J. Understanding resolvin signaling pathways to improve oral health. Int. J. Mol. Sci 2013, 14, 5501–5518. [Google Scholar]
  13. Pullikuth, A.K.; Ozdemir, A.; Cardenas, D.; Bailey, E.; Sherman, N.E.; Pfister, K.K.; Catling, A.D. Epidermal growth factor stimulates extracellular-signal regulated kinase phosphorylation of a novel site on cytoplasmic dynein intermediate chain 2. Int. J. Mol. Sci 2013, 14, 3595–3620. [Google Scholar]
  14. Ceresa, B.P. Spatial regulation of epidermal growth factor receptor signaling by endocytosis. Int. J. Mol. Sci 2013, 14, 72–87. [Google Scholar]
  15. Weissenbacher, T.; Vrekoussis, T.; Roeder, D.; Makrigiannakis, A.; Mayr, D.; Ditsch, N.; Friese, K.; Jeschke, U.; Dian, D. Analysis of epithelial growth factor-receptor (egfr) phosphorylation in uterine smooth muscle tumors: Correlation to mucin-1 and galectin-3 expression. Int. J. Mol. Sci 2013, 14, 4783–4792. [Google Scholar]
  16. Hunter, M.P.; Russo, A.; O’Bryan, J.P. Emerging roles for intersectin (ITSN) in regulating signaling and disease pathways. Int. J. Mol. Sci 2013, 14, 7829–7852. [Google Scholar]
  17. Muha, V.; Muller, H.A. Functions and mechanisms of fibroblast growth factor (FGF) signalling in Drosophila melanogaster. Int. J. Mol. Sci 2013, 14, 5920–5937. [Google Scholar]
  18. Conidi, A.; van den Berghe, V.; Huylebroeck, D. Aptamers and their potential to selectively target aspects of EGF, Wnt/beta-Catenin and TGFbeta-Smad family signaling. Int. J. Mol. Sci 2013, 14, 6690–6719. [Google Scholar]
  19. Cattaneo, F.; Parisi, M.; Ammendola, R. Distinct signaling cascades elicited by different formyl Peptide receptor 2 (FPR2) agonists. Int. J. Mol. Sci 2013, 14, 7193–7230. [Google Scholar]
  20. Trincavelli, M.L.; da Pozzo, E.; Ciampi, O.; Cuboni, S.; Daniele, S.; Abbracchio, M.P.; Martini, C. Regulation of erythropoietin receptor activity in endothelial cells by different erythropoietin (EPO) derivatives: An in vitro study. Int. J. Mol. Sci 2013, 14, 2258–2281. [Google Scholar]
  21. Hänel, K.H.; Cornelissen, C.; Luscher, B.; Baron, J.M. Cytokines and the skin barrier. Int. J. Mol. Sci 2013, 14, 6720–6745. [Google Scholar]
  22. Du, J.; Xu, R. RORalpha, a potential tumor suppressor and therapeutic target of breast cancer. Int. J. Mol. Sci 2012, 13, 15755–15766. [Google Scholar]
  23. Micaroni, M.; Malquori, L. Overlapping ATP2C1 and ASTE1 genes in human genome: Implications for SPCA1 expression? Int. J. Mol. Sci 2013, 14, 674–683. [Google Scholar]
  24. Suhr, F.; Gehlert, S.; Grau, M.; Bloch, W. Skeletal muscle function during exercise-fine-tuning of diverse subsystems by nitric oxide. Int. J. Mol. Sci 2013, 14, 7109–7139. [Google Scholar]
  25. Sprenger, J.U.; Nikolaev, V.O. Biophysical techniques for detection of cAMP and cGMP in living cells. Int. J. Mol. Sci 2013, 14, 8025–8046. [Google Scholar]
  26. Meister, M.; Tomasovic, A.; Banning, A.; Tikkanen, R. Mitogen-activated protein (MAP) kinase scaffolding proteins: A recount. Int. J. Mol. Sci 2013, 14, 4854–4884. [Google Scholar]
  27. Candelori, A.; Luporini, P.; Alimenti, C.; Vallesi, A. Characterization and expression of the gene encoding En-MAPK1, an intestinal cell kinase (ICK)-like kinase activated by the autocrine pheromone-signaling loop in the polar ciliate, Euplotes nobilii. Int. J. Mol. Sci 2013, 14, 7457–7467. [Google Scholar]
  28. Joshi, R.P.; Koretzky, G.A. Diacylglycerol kinases: Regulated controllers of T cell activation, function, and development. Int. J. Mol. Sci 2013, 14, 6649–6673. [Google Scholar]
  29. Sadatomi, D.; Tanimura, S.; Ozaki, K.; Takeda, K. Atypical protein phosphatases: Emerging players in cellular signaling. Int. J. Mol. Sci 2013, 14, 4596–4612. [Google Scholar]
  30. Moretti, J.; Brou, C. Ubiquitinations in the notch signaling pathway. Int. J. Mol. Sci 2013, 14, 6359–6381. [Google Scholar]
  31. Tong, J.; Wang, Y.; Chang, B.; Zhang, D.; Wang, B. Evidence for the involvement of RhoA signaling in the ethanol-induced increase in intestinal epithelial barrier permeability. Int. J. Mol. Sci 2013, 14, 3946–3960. [Google Scholar]
  32. Wang, C.M.; Yang, W.H. Loss of SUMOylation on ATF3 inhibits proliferation of prostate cancer cells by modulating CCND1/2 activity. Int. J. Mol. Sci 2013, 14, 8367–8380. [Google Scholar]
  33. Corrado, C.; Raimondo, S.; Chiesi, A.; Ciccia, F.; de Leo, G.; Alessandro, R. Exosomes as intercellular signaling organelles involved in health and disease: Basic science and clinical applications. Int. J. Mol. Sci 2013, 14, 5338–5366. [Google Scholar]
  34. Takemiya, T.; Yamagata, K. Intercellular signaling pathway among endothelia, astrocytes and neurons in excitatory neuronal damage. Int. J. Mol. Sci 2013, 14, 8345–8357. [Google Scholar]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert