Editorial of the Special Issue: Signaling Molecules and Signal Transduction in Cells

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.

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 OPEN ACCESS 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 (Ca 2+ )-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].

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.