http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2013 , Hindawi Publishing Corporation . All rights reserved. Mon, 31 Dec 2012 15:53:17 +0000 http://www.hindawi.com/journals/jst/2012/785196/ Donna J. Webb, Claire M. Brown, and Kris A. DeMali Copyright © 2012 Donna J. Webb et al. All rights reserved. Sun, 09 Dec 2012 12:26:18 +0000 http://www.hindawi.com/journals/jst/2012/704247/ Laura Cerchia, Juan-Carlos Martinez Montero, and Parisa Monfared Copyright © 2012 Laura Cerchia et al. All rights reserved. Thu, 29 Nov 2012 09:09:35 +0000 http://www.hindawi.com/journals/jst/2012/460842/ Satellite cells can maintain or repair muscle because they possess stem cell properties, making them a valuable option for cell therapy. However, cell transplants into skeletal muscle of patients with muscular dystrophy are limited by donor cell attachment, migration, and survival in the host tissue. Cells used for therapy are selected based on specific markers present in the plasma membrane. Although many markers have been identified, there is a need to find a marker that is expressed at different states in satellite cells, activated, quiescent, or differentiated cell. Furthermore, the marker has to be present in human tissue. Recently we reported that the plasma membrane α2δ1 protein is involved in cell attachment and migration in myoblasts. The α2δ1 subunit forms a part of the L-type voltage-dependent calcium channel in adult skeletal muscle. We found that the α2δ1 subunit is expressed in the majority of newly isolated satellite cells and that it appears earlier than the α1 subunits and at higher levels than the β or γ subunits. We also found that those cells that expressed α2δ1 would differentiate into muscle cells. This evidence indicates that the α2δ1 may be used as a marker of satellite cells that will differentiate into muscle. Tammy Tamayo, Liliana Grajales, and Jesús García Copyright © 2012 Tammy Tamayo et al. All rights reserved. Sun, 11 Nov 2012 15:13:44 +0000 http://www.hindawi.com/journals/jst/2012/181560/ In sexual reproduction, two gamete cells (i.e., egg and sperm) fuse (fertilization) to create a newborn with a genetic identity distinct from those of the parents. In the course of these developmental processes, a variety of signal transduction events occur simultaneously in each of the two gametes, as well as in the fertilized egg/zygote/early embryo. In particular, a growing body of knowledge suggests that the tyrosine kinase Src and/or other protein-tyrosine kinases are important elements that facilitate successful implementation of the aforementioned processes in many animal species. In this paper, we summarize recent findings on the roles of protein-tyrosine phosphorylation in many sperm-related processes (from spermatogenesis to epididymal maturation, capacitation, acrosomal exocytosis, and fertilization). Takashi W. Ijiri, A. K. M. Mahbub Hasan, and Ken-ichi Sato Copyright © 2012 Takashi W. Ijiri et al. All rights reserved. Sun, 14 Oct 2012 12:18:22 +0000 http://www.hindawi.com/journals/jst/2012/597214/ Influx of calcium through voltage-dependent channels regulates processes throughout the nervous system. Specifically, influx through L-type channels plays a variety of roles in early neuronal development and is commonly modulated by G-protein-coupled receptors such as GABAB receptors. Of the four isoforms of L-type channels, only CaV1.2 and CaV1.3 are predominately expressed in the nervous system. Both isoforms are inhibited by the same pharmacological agents, so it has been difficult to determine the role of specific isoforms in physiological processes. In the present study, Western blot analysis and confocal microscopy were utilized to study developmental expression levels and patterns of CaV1.2 and CaV1.3 in the CA1 region of rat hippocampus. Steady-state expression of CaV1.2 predominated during the early neonatal period decreasing by day 12. Steady-state expression of CaV1.3 was low at birth and gradually rose to adult levels by postnatal day 15. In immunohistochemical studies, antibodies against CaV1.2 and CaV1.3 demonstrated the highest intensity of labeling in the proximal dendrites at all ages studied (P1–72). Immunohistochemical studies on one-week-old hippocampi demonstrated significantly more colocalization of GABAB receptors with CaV1.2 than with CaV1.3, suggesting that modulation of L-type calcium current in early development is mediated through CaV1.2 channels. Audra A. Kramer, Nicholas E. Ingraham, Emily J. Sharpe, and Michelle Mynlieff Copyright © 2012 Audra A. Kramer et al. All rights reserved. Tue, 09 Oct 2012 15:55:52 +0000 http://www.hindawi.com/journals/jst/2012/204236/ Estrogen and growth factors play a major role in uterine leiomyoma (UtLM) growth possibly through interactions of receptor tyrosine kinases (RTKs) and estrogen receptor-alpha (ER) signaling. We determined the genomic and nongenomic effects of 17-estradiol (E2) on IGF-IR/MAPKp44/42 signaling and gene expression in human UtLM cells with intact or silenced IGF-IR. Analysis by RT2 Profiler PCR-array showed genes involved in IGF-IR/MAPK signaling were upregulated in UtLM cells by E2 including cyclin D kinases, MAPKs, and MAPK kinases; RTK signaling mediator, GRB2; transcriptional factors ELK1 and E2F1; CCNB2 involved in cell cycle progression, proliferation, and survival; and COL1A1 associated with collagen synthesis. Silencing (si)IGF-IR attenuated the above effects and resulted in upregulation of different genes, such as transcriptional factor ETS2; the tyrosine kinase receptor, EGFR; and DLK1 involved in fibrosis. E2 rapidly activated IGF-IR/MAPKp44/42 signaling nongenomically and induced phosphorylation of ER at ser118 in cells with a functional IGF-IR versus those without. E2 also upregulated IGF-I gene and protein expression through a prolonged genomic event. These results suggest a pivotal role of IGF-IR and possibly other RTKs in mediating genomic and nongenomic hormone receptor interactions and signaling in fibroids and provide novel genes and targets for future intervention and prevention strategies. Linda Yu, Alicia B. Moore, Lysandra Castro, Xiaohua Gao, Hoang-Long C. Huynh, Michelle Klippel, Norris D. Flagler, Yi Lu, Grace E. Kissling, and Darlene Dixon Copyright © 2012 Linda Yu et al. All rights reserved. Thu, 27 Sep 2012 18:53:44 +0000 http://www.hindawi.com/journals/jst/2012/951497/ Pulmonary circulation is an important circulatory system in which the body brings in oxygen. Pulmonary arterial hypertension (PAH) is a progressive and fatal disease that predominantly affects women. Sustained pulmonary vasoconstriction, excessive pulmonary vascular remodeling, in situ thrombosis, and increased pulmonary vascular stiffness are the major causes for the elevated pulmonary vascular resistance (PVR) in patients with PAH. The elevated PVR causes an increase in afterload in the right ventricle, leading to right ventricular hypertrophy, right heart failure, and eventually death. Understanding the pathogenic mechanisms of PAH is important for developing more effective therapeutic approach for the disease. An increase in cytosolic free concentration () in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC migration and proliferation which lead to pulmonary vascular wall thickening and remodeling. It is thus pertinent to define the pathogenic role of signaling in pulmonary vasoconstriction and PASMC proliferation to develop new therapies for PAH. in PASMC is increased by influx through channels in the plasma membrane and by release or mobilization from the intracellular stores, such as sarcoplasmic reticulum (SR) or endoplasmic reticulum (ER). There are two entry pathways, voltage-dependent influx through voltage-dependent channels (VDCC) and voltage-independent influx through store-operated Ca2+ channels (SOC) and receptor-operated channels (ROC). This paper will focus on the potential role of VDCC, SOC, and ROC in the development and progression of sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling in PAH. Ruby A. Fernandez, Premanand Sundivakkam, Kimberly A. Smith, Amy S. Zeifman, Abigail R. Drennan, and Jason X.-J. Yuan Copyright © 2012 Ruby A. Fernandez et al. All rights reserved. Sun, 23 Sep 2012 15:12:48 +0000 http://www.hindawi.com/journals/jst/2012/902854/ Gliomas are the most common tumor in the central nervous system. High-grade glioblastomas are characterized by their high invasiveness and resistance to radiotherapy, leading to high recurrence rate and short median survival despite radical surgical resection. Characterizations of gliomas at molecular level have revealed aberrations of various growth factor receptors, receptor tyrosine kinases, and tumor suppressor genes that lead to deregulation of multiple signaling pathways, thereby contributing to abnormal proliferation, invasion, and resistance to apoptosis in cancer cells. Recently, accumulating evidence points to the emerging role of axon guidance molecules in glioma progression. Notably, many signaling events harnessed by guidance molecules to regulate cell migration and axon navigation during development are also found to be involved in the modulation of deregulated pathways in gliomas. This paper focused on the signalings triggered by the guidance molecule semaphorins and their receptors plexins and neuropilins, and how their crosstalk with oncogenic pathways in gliomas might modulate cancer progression. The emerging role of semaphorins and plexins as tumor suppressors or oncogenes is also discussed. Janice Wai Sze Law and Alan Yiu Wah Lee Copyright © 2012 Janice Wai Sze Law and Alan Yiu Wah Lee. All rights reserved. Wed, 05 Sep 2012 11:43:35 +0000 http://www.hindawi.com/journals/jst/2012/248759/ Interactions between the extracellular matrix (ECM) and integrin receptors trigger structural and functional bonds between the cell microenvironment and the cytoskeleton. Such connections are essential for adhesion structure integrity and are key players in regulating transduction of specific intracellular signals, which in turn regulate the organization of the cell microenvironment and, consequently, cell function. The RGD peptide-dependent integrins represent a key subgroup of ECM receptors involved in the maintenance of epithelial homeostasis. Here we review recent findings on RGD-dependent ECM-integrin interactions and their roles in human intestinal epithelial crypt cells. Yannick D. Benoit, Jean-François Groulx, David Gagné, and Jean-François Beaulieu Copyright © 2012 Yannick D. Benoit et al. All rights reserved. Mon, 03 Sep 2012 14:31:51 +0000 http://www.hindawi.com/journals/jst/2012/483796/ Protein-tyrosine phosphorylation, which is catalyzed by protein-tyrosine kinase (PTK), plays a pivotal role in a variety of cellular functions related to health and disease. The discovery of the viral oncogene Src (v-Src) and its cellular nontransforming counterpart (c-Src), as the first example of PTK, has opened a window to study the relationship between protein-tyrosine phosphorylation and the biology and medicine of cancer. In this paper, we focus on the roles played by Src and other PTKs in cancer cell-specific behavior, that is, evasion of apoptosis or cell death under stressful extracellular and/or intracellular microenvironments (i.e., hypoxia, anoikis, hypoglycemia, and serum deprivation). A. K. M. Mahbub Hasan, Takashi Ijiri, and Ken-ichi Sato Copyright © 2012 A. K. M. Mahbub Hasan et al. All rights reserved. Tue, 28 Aug 2012 13:49:02 +0000 http://www.hindawi.com/journals/jst/2012/645721/ Ventricular myocytes deficient in endothelial nitric oxide synthase (NOS3−/−) exhibit prolonged action potential (AP) duration and enhanced spontaneous activity (early and delayed afterdepolarizations) during β-adrenergic (β-AR) stimulation. Studies have shown that nitric oxide is able to regulate various K+ channels. Our objective was to examine if NOS3-/- myocytes had altered K+ currents. APs, transient outward (𝐼to), sustained (𝐼Ksus), and inward rectifier (𝐼K1) K+ currents were measured in NOS3-/- and wild-type (WT) myocytes. During β-AR stimulation, AP duration (measured as 90% repolarization-APD90) was prolonged in NOS3−/− compared to WT myocytes. Nevertheless, we did not observe differences in 𝐼to, 𝐼Ksus, or 𝐼K1 between WT and NOS3−/− myocytes. Our previous work showed that NOS3−/− myocytes had a greater Ca2+ influx via L-type Ca2+ channels with β-AR stimulation. Thus, we measured β-AR-stimulated SR Ca2+ load and found a greater increase in NOS3−/− versus WT myocytes. Hence, our data suggest that the prolonged AP in NOS3−/− myocytes is not due to changes in 𝐼to, 𝐼Ksus, or 𝐼K1. Furthermore, the increase in spontaneous activity in NOS3−/− myocytes may be due to a greater increase in SR Ca2+ load. This may have important implications for heart failure patients, where arrhythmias are increased and NOS3 expression is decreased. Honglan Wang, Ingrid M. Bonilla, Xin Huang, Quanhua He, Mark J. Kohr, Cynthia A. Carnes, and Mark T. Ziolo Copyright © 2012 Honglan Wang et al. All rights reserved. Mon, 13 Aug 2012 07:59:40 +0000 http://www.hindawi.com/journals/jst/2012/619747/ Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels were first reported in heart cells and are recently known to be involved in a variety of neural functions in healthy and diseased brains. HCN channels generate inward currents when the membrane potential is hyperpolarized. Voltage dependence of HCN channels is regulated by intracellular signaling cascades, which contain cyclic AMP, PIP2, and TRIP8b. In addition, voltage-gated potassium channels have a strong influence on HCN channel activity. Because of these funny features, HCN channel currents, previously called funny currents, can have a wide range of functions that are determined by a delicate balance of modulatory factors. These multifaceted features also make it difficult to predict and elucidate the functional role of HCN channels in actual neurons. In this paper, we focus on the impacts of HCN channels on neural activity. The functions of HCN channels reported previously will be summarized, and their mechanisms will be explained by using numerical simulation of simplified model neurons. Daisuke Kase and Keiji Imoto Copyright © 2012 Daisuke Kase and Keiji Imoto. All rights reserved. Thu, 26 Jul 2012 13:08:22 +0000 http://www.hindawi.com/journals/jst/2012/473410/ Intracellular nitric oxide (NOi) is a physiological regulator of excitation-contraction coupling, but is also involved in the development of cardiac dysfunction during hypertrophy and heart failure. To determine whether contractile activity regulates nitric oxide synthase (NOS) expression, spontaneously contracting, neonatal rat ventricular myocytes (NRVM) were treat with L-type calcium channel blockers (nifedipine and verapamil) or myosin II ATPase inhibitors (butanedione monoxime (BDM) and blebbistatin) to produce contractile arrest. Both types of inhibitors significantly reduced iNOS but not eNOS expression, and also reduced NOi production. Inhibiting contractile activity also reduced focal adhesion kinase (FAK) and AKT phosphorylation. Contraction-induced iNOS expression required FAK and phosphatidylinositol 3-kinase (PI(3)K), as both PF573228 and LY294002 (10 μM, 24 h) eliminated contraction-induced iNOS expression. Similarly, shRNAs specific for FAK (shFAK) caused FAK knockdown, reduced AKT phosphorylation at T308 and S473, and reduced iNOS expression. In contrast, shRNA-mediated knockdown of PYK2, the other member of the FAK-family of protein tyrosine kinases, had much less of an effect. Conversely, overexpression of a constitutively active form of FAK (CD2-FAK) or AKT (Myr-AKT) reversed the inhibitory effect of BDM on iNOS expression and NOi production. Thus, contraction-induced iNOS expression and NOi production in NRVM are mediated via a FAK-PI(3)K-AKT signaling pathway. Miensheng Chu, Yevgeniya Koshman, Rekha Iyengar, Taehoon Kim, Brenda Russell, and Allen M. Samarel Copyright © 2012 Miensheng Chu et al. All rights reserved. Wed, 25 Jul 2012 08:26:37 +0000 http://www.hindawi.com/journals/jst/2012/192142/ Mammary gland ion transport is essential for lactation and is regulated by prolactin and glucocorticoids. This study delineates the roles of prolactin receptors (PRLR) and long-term prolactin and dexamethasone (P-D)-mediation of [Ca2+]i and Cl− transport in HC-11 cells. P-D (24 h) suppressed ATP-induced [Ca2+]i. This may be due to decreased Ca2+ entry since P-D decreased transient receptor potential channel 3 (TRPC3) but not secretory pathway Ca2+-ATPase 2 (SPCA2) mRNA. ATP increased Cl− transport, measured by iodide (I−) efflux, in control and P-D-treated cells. P-D enhanced I− efflux response to cAMP secretagogues without altering Cl− channels or NKCC cotransporter expression. HC-11 cells contain only the long form of PRLR (PRLR-L). Since the short isoform, PRLR-S, is mammopoietic, we determined if transfecting PRLR-S (rs) altered PRLR-L-mediated Ca2+ and Cl− transport. Untreated rs cells showed an attenuated [Ca2+]i response to ATP with no further response to P-D, in contrast to vector-transfected (vtc) controls. P-D inhibited TRPC3 in rs and vtc cells but increased SPCA2 only in rs cells. As in wild-type, cAMP-stimulated Cl− transport, in P-D-treated vtc and rs cells. In summary, 24 h P-D acts via PRLR-L to attenuate ATP-induced [Ca2+]i and increase cAMP-activated Cl− transport. PRLR-S fine-tunes these responses underscoring its mammopoietic action. Utchariya Anantamongkol, Mei Ao, Jayashree Sarathy nee Venkatasubramanian, Y. Sangeeta Devi, Nateetip Krishnamra, and Mrinalini C. Rao Copyright © 2012 Utchariya Anantamongkol et al. All rights reserved. Thu, 19 Jul 2012 13:48:26 +0000 http://www.hindawi.com/journals/jst/2012/296450/ Cell adhesion to the extracellular matrix (ECM) is essential for cell migration, proliferation, and embryonic development. Cells can contact the ECM through a wide range of matrix contact structures such as focal adhesions, podosomes, and invadopodia. Although they are different in structural design and basic function, they share common remodeling proteins such as integrins, talin, paxillin, and the tyrosine kinases FAK, Pyk2, and Src. In this paper, we compare and contrast the basic organization and role of focal adhesions, podosomes, and invadopodia in different cells. In addition, we discuss the role of the tyrosine kinases, FAK, Pyk2, and Src, which are critical for the function of the different adhesion structures. Finally, we discuss the essential role of these tyrosine kinases from the perspective of human diseases. Pierre P. Eleniste and Angela Bruzzaniti Copyright © 2012 Pierre P. Eleniste and Angela Bruzzaniti. All rights reserved. Wed, 18 Jul 2012 08:37:51 +0000 http://www.hindawi.com/journals/jst/2012/123253/ Anaplastic lymphoma kinase (ALK) was first identified in 1994 with the discovery that the gene encoding for this kinase was involved in the t(2;5)(p23;q35) chromosomal translocation observed in a subset of anaplastic large cell lymphoma (ALCL). The NPM-ALK fusion protein generated by this translocation is a constitutively active tyrosine kinase, and much research has focused on characterizing the signalling pathways and cellular activities this oncoprotein regulates in ALCL. We now know about the existence of nearly 20 distinct ALK translocation partners, and the fusion proteins resulting from these translocations play a critical role in the pathogenesis of a variety of cancers including subsets of large B-cell lymphomas, nonsmall cell lung carcinomas, and inflammatory myofibroblastic tumours. Moreover, the inhibition of ALK has been shown to be an effective treatment strategy in some of these malignancies. In this paper we will highlight malignancies where ALK translocations have been identified and discuss why ALK fusion proteins are constitutively active tyrosine kinases. Finally, using ALCL as an example, we will examine three key signalling pathways activated by NPM-ALK that contribute to proliferation and survival in ALCL. Joel D. Pearson, Jason K. H. Lee, Julinor T. C. Bacani, Raymond Lai, and Robert J. Ingham Copyright © 2012 Joel D. Pearson et al. All rights reserved. Tue, 17 Jul 2012 18:50:41 +0000 http://www.hindawi.com/journals/jst/2012/956958/ Gliomas are the most common type of primary brain tumor. Although tremendous progress has been achieved in the recent years in the diagnosis and treatment, its molecular etiology remains unknown. In this regard, epigenetics represents a new approach to study the mechanisms that control gene expression and function without changing the sequence of the genome. In the present paper we describe the main findings about the alterations of cell signaling pathways in the most aggressive glioma in the adult population, namely, glioblastoma, in which epigenetic mechanisms and the emerging role of cancer stem cell play a crucial function in the development of new biomarkers for its detection and prognosis and the corresponding development of new pharmacological strategies. Raúl Alelú-Paz, Nadia Ashour, Ana González-Corpas, and Santiago Ropero Copyright © 2012 Raúl Alelú-Paz et al. All rights reserved. Tue, 17 Jul 2012 09:22:58 +0000 http://www.hindawi.com/journals/jst/2012/597915/ The angiogenesis process is a key event for glioma survival, malignancy and growth. The start of angiogenesis is mediated by a cascade of intratumoural events: alteration of the microvasculature network; a hypoxic microenvironment; adaptation of neoplastic cells and synthesis of pro-angiogenic factors. Due to a chaotic blood flow, a consequence of an aberrant microvasculature, tissue hypoxia phenomena are induced. Hypoxia inducible factor 1 is a major regulator in glioma invasiveness and angiogenesis. Clones of neoplastic cells with stem cell characteristics are selected by HIF-1. These cells, called “glioma stem cells” induce the synthesis of vascular endothelial growth factor. This factor is a pivotal mediator of angiogenesis. To elucidate the role of these angiogenic mediators during glioma growth, we have used a rat endogenous glioma model. Gliomas induced by prenatal ENU administration allowed us to study angiogenic events from early to advanced tumour stages. Events such as microvascular aberrations, hypoxia, GSC selection and VEGF synthesis may be studied in depth. Our data showed that for the treatment of gliomas, developing anti-angiogenic therapies could be aimed at GSCs, HIF-1 or VEGF. The ENU-glioma model can be considered to be a useful option to check novel designs of these treatment strategies. Susana Bulnes, Harkaitz Bengoetxea, Naiara Ortuzar, Enrike G. Argandoña, Álvaro Garcia-Blanco, Irantzu Rico-Barrio, and José V. Lafuente Copyright © 2012 Susana Bulnes et al. All rights reserved. Mon, 16 Jul 2012 15:42:38 +0000 http://www.hindawi.com/journals/jst/2012/361721/ The poor or lack of injured adult central nervous system (CNS) axon regeneration results in devastating consequences and poor functional recovery. The interplay between the intrinsic and extrinsic factors contributes to robust inhibition of axon regeneration of injured CNS neurons. The insufficient or lack of trophic support for injured neurons is considered as one of the major obstacles contributing to their failure to survive and regrow their axons after injury. In the CNS, many of the signalling pathways associated with neuronal survival and axon regeneration are regulated by several classes of receptor tyrosine kinases (RTK) that respond to a variety of ligands. This paper highlights and summarises the most relevant recent findings pertinent to different classes of the RTK family of molecules, with a particular focus on elucidating their role in CNS axon regeneration. Vasanthy Vigneswara, Sarina Kundi, and Zubair Ahmed Copyright © 2012 Vasanthy Vigneswara et al. All rights reserved. Sun, 15 Jul 2012 15:18:52 +0000 http://www.hindawi.com/journals/jst/2012/931215/ To maintain cellular homeostasis, cells are equipped with precise systems that trigger the appropriate stress responses. Mitochondria not only provide cellular energy but also integrate stress response signaling pathways, including those regulating cell death. Several lines of evidence suggest that the mitochondrial proteins that function in this process, such as Bcl-2 family proteins in apoptosis and phosphoglycerate mutase family member 5 (PGAM5) in necroptosis, are regulated by several kinases. It has also been suggested that the phosphorylation-dependent regulation of mitochondrial fission machinery, dynamin-related protein 1 (Drp1), facilitates appropriate cellular stress responses. However, mitochondria themselves are also damaged by various stresses. To avoid the deleterious effects exerted by damaged mitochondria, cells remove these mitochondria in a selective autophagic degradation process called mitophagy. Interestingly, several kinases, such as PTEN-induced putative kinase 1 (PINK1) in mammals and stress-responsive mitogen-activated protein (MAP) kinases in yeast, have recently been shown to be involved in mitophagy. In this paper, we focus on the phosphorylation-dependent regulation of mitochondrial proteins and discuss the roles of this regulation in the mitochondrial and cellular stress responses. Yusuke Kanamaru, Shiori Sekine, Hidenori Ichijo, and Kohsuke Takeda Copyright © 2012 Yusuke Kanamaru et al. All rights reserved. Thu, 12 Jul 2012 09:07:22 +0000 http://www.hindawi.com/journals/jst/2012/125295/ Adherens junctions connect the actin cytoskeleton of neighboring cells through transmembrane cadherin receptors and a network of adaptor proteins. The interactions between these adaptors and cadherin as well as the activity of actin regulators localized to adherens junctions are tightly controlled to facilitate cell junction assembly or disassembly in response to changes in external or internal forces and/or signaling. Phosphorylation of tyrosine, serine, or threonine residues acts as a switch on the majority of adherens junction proteins, turning “on” or “off” their interactions with other proteins and/or their enzymatic activity. Here, we provide an overview of the kinases and phosphatases regulating phosphorylation of adherens junction proteins and bring examples of phosphorylation events leading to the assembly or disassembly of adherens junctions, highlighting the important role of phosphorylation switches in regulating their dynamics. Cristina Bertocchi, Megha Vaman Rao, and Ronen Zaidel-Bar Copyright © 2012 Cristina Bertocchi et al. All rights reserved. Wed, 11 Jul 2012 10:58:43 +0000 http://www.hindawi.com/journals/jst/2012/505346/ The Kelch-like 1 protein (KLHL1) is a neuronal actin-binding protein that modulates calcium channel function. It increases the current density of Cav3.2 (𝛼1H) calcium channels via direct interaction with 𝛼1H and actin-F, resulting in biophysical changes in Cav3.2 currents and an increase in recycling endosomal activity with subsequent increased 𝛼1H channel number at the plasma membrane. Interestingly, removal of the actin-binding Kelch motif (ΔKelch) prevents the increase in Cav3.2 current density seen with wild-type KLHL1 when tested with normal square pulse protocols but does not preclude the effect when tested using action potential waveforms (AP). Here, we dissected the kinetic properties of the AP waveform that confer the mutant Kelch the ability to interact with Cav3.2 and induce an increase in calcium influx. We modified the action potential waveform by altering the slopes of repolarization and/or recovery from hyperpolarization or by changing the duration of the depolarization plateau or the hyperpolarization phase and tested the modulation of Cav3.2 by the mutant ΔKelch. Our results show that the recovery phase from hyperpolarization phase determines the conformational changes that allow the 𝛼1H subunit to properly interact with mutant KLHL1 lacking its actin-binding Kelch domains, leading to increased Ca influx. Kelly A. Aromolaran, Kelly A. Benzow, Leanne L. Cribbs, Michael D. Koob, and Erika S. Piedras-Rentería Copyright © 2012 Kelly A. Aromolaran et al. All rights reserved. Sun, 08 Jul 2012 08:25:59 +0000 http://www.hindawi.com/journals/jst/2012/483040/ Currently, antiangiogenic agents are routinely used for the treatment of patients with glioma. However, despite advances in pharmacological and surgical therapy, glioma remains an incurable disease. Indeed, the formation of an abnormal tumor vasculature and the invasion of glioma cells along neuronal tracts are proposed to comprise the major factors that are attributed to the therapeutic resistance of these tumors. The development of curative therapeutic modalities for the treatment of glioma requires further investigation of the molecular mechanisms regulating angiogenesis and invasion. In this review, we discuss the molecular characteristics of angiogenesis and invasion in human malignant glioma, we present several available drugs that are used or can potentially be utilized for the inhibition of angiogenesis in glioma, and we focus our attention on the key mediators of the molecular mechanisms underlying the resistance of glioma to antiangiogenic therapy. Valentina Cea, Carlo Sala, and Chiara Verpelli Copyright © 2012 Valentina Cea et al. All rights reserved. Thu, 05 Jul 2012 13:23:49 +0000 http://www.hindawi.com/journals/jst/2012/570183/ Cytotoxic necrotizing factors (CNFs) encompass a class of autotransporter toxins produced by uropathogenic E. coli (CNF1) or Y. pseudotuberculosis (CNFy). CNF toxins deamidate and thereby constitutively activate RhoA, Rac1, and Cdc42. In this study, the effects of CNF1 on cell-matrix adhesion are analysed using functional cell-adhesion assays. CNF1 strongly increased cell-matrix binding of suspended Hela cells and decreased the susceptibly of cells to trypsin-induced cell detachment. Increased cell-matrix binding was also observed upon treatment of Hela cells with isomeric CNFy, that specifically deamidates RhoA. Increased cell-matrix binding thus appears to depend on RhoA deamidation. In contrast, increased cell spreading was specifically observed upon CNF1 treatment, suggesting that it rather depended on Rac1/Cdc42 deamidation. Increased cell-matrix adhesion is further presented to result in reduced cell migration of adherent cells. In contrast, migration of suspended cells was not affected upon treatment with CNF1 or CNFy. CNF1 and CNFy thus reduced cell migration specifically under the condition of pre-established cell-matrix adhesion. Martin May, Tanja Kolbe, Tianbang Wang, Gudula Schmidt, and Harald Genth Copyright © 2012 Martin May et al. All rights reserved. Thu, 28 Jun 2012 11:07:09 +0000 http://www.hindawi.com/journals/jst/2012/529179/ Cellular dynamics are controlled by key signaling molecules such as cAMP-dependent protein kinase (PKA) and protein kinase C (PKC). AKAP12/SSeCKS/Gravin (AKAP12) is a scaffold protein for PKA and PKC which controls actin-cytoskeleton reorganization in a spatiotemporal manner. AKAP12 also acts as a tumor suppressor which regulates cell-cycle progression and inhibits Src-mediated oncogenic signaling and cytoskeletal pathways. Reexpression of AKAP12 causes cell flattening, reorganization of the actin cytoskeleton, and the production of normalized focal adhesion structures. Downregulation of AKAP12 induces the formation of thickened, longitudinal stress fibers and the proliferation of adhesion complexes. AKAP12-null mouse embryonic fibroblasts exhibit hyperactivation of PKC, premature cellular senescence, and defects in cytokinesis, relating to the loss of PKC scaffolding activity by AKAP12. AKAP12-null mice exhibit increased cell senescence and increased susceptibility to carcinogen-induced oncogenesis. The paper describes the regulatory and scaffolding functions of AKAP12 and how it regulates cell adhesion, signaling, and oncogenic suppression. Shin Akakura and Irwin H. Gelman Copyright © 2012 Shin Akakura and Irwin H. Gelman. All rights reserved. Mon, 25 Jun 2012 11:43:31 +0000 http://www.hindawi.com/journals/jst/2012/649079/ A significant amount of evidence suggests that the p38-mitogen-activated protein kinase (MAPK) signalling cascade plays a crucial role in synaptic plasticity and in neurodegenerative diseases. In this review we will discuss the cellular localisation and activation of p38 MAPK and the recent advances on the molecular and cellular mechanisms of its substrates: MAPKAPK 2 (MK2) and tau protein. In particular we will focus our attention on the understanding of the p38 MAPK-MK2 and p38 MAPK-tau activation axis in controlling neuroinflammation, actin remodelling and tau hyperphosphorylation, processes that are thought to be involved in normal ageing as well as in neurodegenerative diseases. We will also give some insight into how elucidating the precise role of p38 MAPK-MK2 and p38 MAPK-tau signalling cascades may help to identify novel therapeutic targets to slow down the symptoms observed in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Sônia A. L. Corrêa and Katherine L. Eales Copyright © 2012 Sônia A. L. Corrêa and Katherine L. Eales. All rights reserved. Mon, 18 Jun 2012 14:29:09 +0000 http://www.hindawi.com/journals/jst/2012/519807/ Diffuse gliomas are the most frequent brain tumor in adults. This group of brain neoplasms, ranging from histologically benign to aggressive malignant forms, represents a challenge in modern neurooncology because of the diffuse infiltrative growth pattern and the inherent tendency to relapse as a more malignant tumor. Once the disease achieves the stage of glioblastoma multiforme (GBM), the prognosis of patients is dismal and the median survival time is 15 months. Exhaustive genetic analyses have revealed a variety of deregulated genetic pathways involved in DNA repair, apoptosis, cell migration/adhesion, and cell cycle. Recently, investigation of epigenetic alterations in gliomas has contributed to depict the complexity of the molecular lesions leading to these malignancies. Even though, the efficacy of the state-of-the-art form of chemotherapy in malignant gliomas with temozolomide is based on the methylation-associated silencing of the DNA repair gene MGMT. Nevertheless, the whole scenario including global DNA hypomethylation, aberrant promoter hypermethylation, histone modification, chromatin states, and the role of noncoding RNAs in gliomas has only been partially revealed. We discuss the repercussion of epigenetic alterations underlying deregulated molecular pathways in the pathogenesis and evolution of gliomas and their impact on management of patients. Ramón Martínez Copyright © 2012 Ramón Martínez. All rights reserved. Thu, 14 Jun 2012 12:47:35 +0000 http://www.hindawi.com/journals/jst/2012/804801/ The insulin-like growth factor I receptor (IGF1R) is overexpressed in several forms of human cancer, and it has emerged as an important target for anticancer drug design. Cancer genome sequencing efforts have recently identified three somatic mutations in IGF1R: A1374V, a deletion of S1278 in the C-terminal tail region of the receptor, and M1255I in the C-terminal lobe of the kinase catalytic domain. The possible effects of these mutations on IGF1R activity and biological function have not previously been tested. Here, we tested the effects of the mutations on the in vitro biochemical activity of IGF1R and on major IGF1R signaling pathways in mammalian cells. While the mutations do not affect the intrinsic tyrosine kinase activity of the receptor, we demonstrate that the basal (unstimulated) levels of MAP kinase and Akt activation are increased in the mutants (relative to wild-type IGF1R). We hypothesize that the enhanced signaling potential of these mutants is due to changes in protein-protein interactions between the IGF1R C-terminus and cellular substrates or modulators. Barbara P. Craddock and W. Todd Miller Copyright © 2012 Barbara P. Craddock and W. Todd Miller. All rights reserved. Thu, 14 Jun 2012 08:24:21 +0000 http://www.hindawi.com/journals/jst/2012/412089/ Integrins and other families of cell adhesion receptors are responsible for platelet adhesion and aggregation, which are essential steps for physiological haemostasis, as well as for the development of thrombosis. The modulation of platelet adhesive properties is the result of a complex pattern of inside-out and outside-in signaling pathways, in which the members of the Rap family of small GTPases are bidirectionally involved. This paper focuses on the regulation of the main Rap GTPase expressed in circulating platelets, Rap1b, downstream of adhesion receptors, and summarizes the most recent achievements in the investigation of the function of this protein as regulator of platelet adhesion and thrombus formation. Gianni Francesco Guidetti and Mauro Torti Copyright © 2012 Gianni Francesco Guidetti and Mauro Torti. All rights reserved. Mon, 21 May 2012 14:06:03 +0000 http://www.hindawi.com/journals/jst/2012/735135/ Gliomas are the most common primary central nervous system tumors with a dismal prognosis. Despite recent advances in surgery, radiotherapy, and chemotherapy, current treatment regimens have a modest survival benefit. A crucial challenge is to deliver drugs effectively to invasive glioma cells residing in a sanctuary within the central nervous system. New therapies are essential, and oligonucleotide-based approaches, including antisense, microRNAs, small interfering RNAs, and nucleic acid aptamers, may provide a viable strategy. Thanks to their unique characteristics (low size, good affinity for the target, no immunogenicity, chemical structures that can be easily modified to improve their in vivo applications), these molecules may represent a valid alternative to antibodies particularly to overcome challenges presented by the blood-brain barrier. Here we will discuss recent results on the use of oligonucleotides that will hopefully provide new effective treatment for gliomas. S. Catuogno, C. L. Esposito, C. Quintavalle, G. Condorelli, V. de Franciscis, and L. Cerchia Copyright © 2012 S. Catuogno et al. All rights reserved.