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Daisuke Ito, Atsushi Kumanogoh
Semaphorins were originally identified as axon guidance cues that regulate the functional activity of axons in the nervous system. In addition, accumulating evidence indicates that semaphorins have multiple functions in physiological and pathogenic processes, including vascular development, tumor progression, and immune responses. Sema4A is a semaphorin expressed in immune cells, and is thus termed an "immune semaphorin." Sema4A has four types of receptors: Plexin D family, Plexin B family, Tim-2, and Nrp-1...
October 13, 2016: Cell Adhesion & Migration
Daisuke Yamada, Satoshi Watanabe, Kohichi Kawahara, Takehiko Maeda
Aberrant changes to several signaling pathways because of genetic mutations or increased cytokine production are critical for tumor cells to become malignant. Semaphorin 3A (SEMA3A) acts as a bivalent factor that suppresses or promotes tumor development in different pathological backgrounds. Previously, we showed that SEMA3A positively regulated the proliferative and glycolytic activities of mouse-derived Lewis lung carcinoma (LLC) cells. Plexins A1-A4 (PLXNA1-PLXNA4) are SEMA3A receptors; however, it is not known which subtype is critical for oncogenic SEMA3A signaling...
October 4, 2016: Biochemical and Biophysical Research Communications
Seyun Roh, Da-Som Yang, Sangyun Jeong
Plexins (Plexs) are a large family of phylogenetically conserved guidance receptors that bind specifically to semaphorins (Semas), another large family of guidance molecules. In the Drosophila embryonic central nervous system (CNS), the secreted semaphorins Sema-2a and Sema-2b both act as ligands for PlexB, but mediate mutually independent and opposite functions (repulsive and attractive guidance, respectively). PlexB is also known to regulate motor axon guidance in the embryonic peripheral nervous system (PNS)...
September 13, 2016: International Journal of Developmental Neuroscience
Xueyan Peng, Meagan Moore, Aditi Mathur, Yang Zhou, Huanxing Sun, Ye Gan, Jose D Herazo-Maya, Naftali Kaminski, Xinyuan Hu, Hongyi Pan, Changwan Ryu, Awo Osafo-Addo, Robert J Homer, Carol Feghali-Bostwick, Wassim Fares, Mridu Gulati, Buqu Hu, Chun-Geun Lee, Jack A Elias, Erica L Herzog
Pulmonary fibrosis is a progressive and often fatal condition that is believed to be partially orchestrated by macrophages. Mechanisms that control migration of these cells into and within the lung remain undefined. We evaluated the contributions of the semaphorin receptor, plexin C1 (PLXNC1), and the exocytic calcium sensor, synaptotagmin 7 (Syt7), in these processes. We evaluated the role of PLXNC1 in macrophage migration by using Boyden chambers and scratch tests, characterized its contribution to experimentally induced lung fibrosis in mice, and defined the mechanism for our observations...
September 8, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Ryuhei Maejima, Keiichi Tamai, Takeharu Shiroki, Misa Yokoyama, Rie Shibuya, Mao Nakamura, Kazunori Yamaguchi, Makoto Abue, Tomoyuki Oikawa, Tetsuya Noguchi, Koh Miura, Tsuneaki Fujiya, Ikuro Sato, Katsunori Iijima, Tooru Shimosegawa, Nobuyuki Tanaka, Kennichi Satoh
Semaphorins and their receptors are abnormally expressed in various cancers, but little is known about the expression and function of semaphorin 3E (SEMA3E) and its receptor, plexin D1 (PLXND1), in gastric cancer development or metastasis. We evaluated SEMA3E and PLXND1 expression by quantitative RT-PCR in gastric tissues from 62 patients who underwent gastrectomy and analyzed the correlation between their expression and clinicopathological variables. To assess the function of SEMA3E, we generated human gastric cancer cell lines with suppressed or increased SEMA3E expression...
September 2016: International Journal of Oncology
Da-Som Yang, Seyun Roh, Sangyun Jeong
Plexins (Plexs) comprise a large family of cell surface receptors for semaphorins (Semas) that function as evolutionarily conserved guidance molecules. GTPase activating protein (GAP) activity for Ras family small GTPases has been implicated in plexin signaling cascades through its RasGAP domain. However, little is known about how Ras family GTPases are controlled in vivo by plexin signaling. Here, we found that Drosophila Rap1, a member of the Ras family of GTPases, plays an important role controlling intersegmental nerve b motor axon guidance during neural development...
October 15, 2016: Developmental Biology
Gera Neufeld, Yelena Mumblat, Tatyana Smolkin, Shira Toledano, Inbal Nir-Zvi, Keren Ziv, Ofra Kessler
The semaphorins were initially characterized as axon guidance factors, but have subsequently been implicated also in the regulation of immune responses, angiogenesis, organ formation, and a variety of additional physiological and developmental functions. The semaphorin family contains more then 20 genes divided into 7 subfamilies, all of which contain the signature sema domain. The semaphorins transduce signals by binding to receptors belonging to the neuropilin or plexin families. Additional receptors which form complexes with these primary semaphorin receptors are also frequently involved in semaphorin signaling...
August 17, 2016: Cell Adhesion & Migration
Rachael Barton, Pouyan Khakbaz, Indrani Bera, Jeffery B Klauda, M Kathryn Iovine, Bryan W Berger
Plexins are transmembrane proteins that serve as guidance receptors during angiogenesis, lymphangiogenesis, neuronal development, and zebrafish fin regeneration, with a putative role in cancer metastasis. Receptor dimerization or clustering, induced by extracellular ligand binding but modulated in part by the plexin transmembrane (TM) and juxtamembrane (JM) domains, is thought to drive plexin activity. Previous studies indicate that isolated plexin TM domains interact through a conserved, small-x3-small packing motif, and the cytosolic JM region interacts through a hydrophobic heptad repeat; however, the roles and interplay of these regions in plexin signal transduction remain unclear...
September 6, 2016: Biochemistry
Laurent Jacob, Paul Sawma, Norbert Garnier, Lionel A T Meyer, Justine Fritz, Thomas Hussenet, Caroline Spenlé, Jacky Goetz, Julien Vermot, Aurore Fernandez, Nadège Baumlin, Samia Aci-Sèche, Gertraud Orend, Guy Roussel, Gérard Crémel, Monique Genest, Pierre Hubert, Dominique Bagnard
The neuropilin-plexin receptor complex regulates tumor cell migration and proliferation and thus is an interesting therapeutic target. High expression of neuropilin-1 is indeed associated with a bad prognosis in glioma patients. Q-RTPCR and tissue-array analyses showed here that Plexin-A1 is highly expressed in glioblastoma and that the highest level of expression correlates with the worse survival of patients. We next identified a developmental and tumor-associated pro-angiogenic role of Plexin-A1. Hence, by using molecular simulations and a two-hybrid like assay in parallel with biochemical and cellular assays we developed a specific Plexin-A1 peptidic antagonist disrupting transmembrane domain-mediated oligomerization of the receptor and subsequent signaling and functional activity...
August 5, 2016: Oncotarget
Yi-Chun Kuo, Xuewu Zhang
The regulation of the guidance receptor plexin is incompletely understood. In this issue, Kong et al. (2016) present crystal structures of the full-length extracellular region of class A plexins, revealing its dual role in both autoinhibition and activation.
August 3, 2016: Neuron
Andréanne Blondeau, Jean-François Lucier, Dominick Matteau, Lauralyne Dumont, Sébastien Rodrigue, Pierre-Étienne Jacques, Richard Blouin
BACKGROUND: Recent genetic studies in model organisms, such as Drosophila, C. elegans and mice, have highlighted a critical role for dual leucine zipper kinase (DLK) in neural development and axonal responses to injury. However, exactly how DLK fulfills these functions remains to be determined. Using RNA-seq profiling, we evaluated the global changes in gene expression that are caused by shRNA-mediated knockdown of endogenous DLK in differentiated Neuro-2a neuroblastoma cells. RESULTS: Our analysis led to the identification of numerous up- and down-regulated genes, among which several were found to be associated with system development and axon guidance according to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, respectively...
2016: Neural Development
Frankie Hang Fung Lee, Ping Su, Yu-Feng Xie, Kyle Ethan Wang, Qi Wan, Fang Liu
GluA2-containing AMPA receptors (AMPARs) play a critical role in various aspects of neurodevelopment. However, the molecular mechanisms underlying these processes are largely unknown. We report here that the interaction between GluA2 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is necessary for neuron and cortical development. Using an interfering peptide (GluA2-G-Gpep) that specifically disrupts this interaction, we found that primary neuron cultures with peptide treatment displayed growth cone development deficits, impairment of axon formation, less dendritic arborization and lower spine protrusion density...
2016: Scientific Reports
Elena E Grintsevich, Hunkar Gizem Yesilyurt, Shannon K Rich, Ruei-Jiun Hung, Jonathan R Terman, Emil Reisler
Numerous cellular functions depend on actin filament (F-actin) disassembly. The best-characterized disassembly proteins, the ADF (actin-depolymerizing factor)/cofilins (encoded by the twinstar gene in Drosophila), sever filaments and recycle monomers to promote actin assembly. Cofilin is also a relatively weak actin disassembler, posing questions about mechanisms of cellular F-actin destabilization. Here we uncover a key link to targeted F-actin disassembly by finding that F-actin is efficiently dismantled through a post-translational-mediated synergism between cofilin and the actin-oxidizing enzyme Mical...
August 2016: Nature Cell Biology
Sa Kan Yoo, Heath G Pascoe, Telmo Pereira, Shu Kondo, Antonio Jacinto, Xuewu Zhang, Iswar K Hariharan
In most multicellular organisms, homeostasis is contingent upon maintaining epithelial integrity. When unanticipated insults breach epithelial barriers, dormant programmes of tissue repair are immediately activated. However, many of the mechanisms that repair damaged epithelia remain poorly characterized. Here we describe a role for Plexin A (PlexA), a protein with particularly well-characterized roles in axonal pathfinding, in the healing of damaged epithelia in Drosophila. Semaphorins, which are PlexA ligands, also regulate tissue repair...
2016: Nature Communications
Donatella Valdembri, Donatella Regano, Federica Maione, Enrico Giraudo, Guido Serini
Secreted class 3 semaphorins (Sema3), which signal through holoreceptor complexes that are formed by different subunits, such as neuropilins (Nrps), proteoglycans, and plexins, were initially characterized as fundamental regulators of axon guidance during embryogenesis. Subsequently, Sema3A, Sema3C, Sema3D, and Sema3E were discovered to play crucial roles in cardiovascular development, mainly acting through Nrp1 and Plexin D1, which funnels the signal of multiple Sema3 in vascular endothelial cells. Mechanistically, Sema3 proteins control cardiovascular patterning through the enzymatic GTPase-activating-protein activity of the cytodomain of Plexin D1, which negatively regulates the function of Rap1, a small GTPase that is well-known for its ability to drive vascular morphogenesis and to elicit the conformational activation of integrin adhesion receptors...
July 20, 2016: Cell Adhesion & Migration
Tobias Eckle
No abstract text is available yet for this article.
August 2016: Critical Care Medicine
Sabrina Curreli, Bin Sheng Wong, Olga Latinovic, Konstantinos Konstantopoulos, Nicholas M Stamatos
Class 3 semaphorins (Semas) are soluble proteins that are well recognized for their role in guiding axonal migration during neuronal development. In the immune system, Sema3A has been shown to influence murine dendritic cell (DC) migration by signaling through a neuropilin (NRP)-1/plexin-A1 coreceptor axis. Potential roles for class 3 Semas in human DCs have yet to be described. We tested the hypothesis that Sema3A, -3C, and -3F, each with a unique NRP-1 and/or NRP-2 binding specificity, influence human DC migration...
July 12, 2016: Journal of Leukocyte Biology
Youxin Kong, Bert J C Janssen, Tomas Malinauskas, Vamshidhar R Vangoor, Charlotte H Coles, Rainer Kaufmann, Tao Ni, Robert J C Gilbert, Sergi Padilla-Parra, R Jeroen Pasterkamp, E Yvonne Jones
Class A plexins (PlxnAs) act as semaphorin receptors and control diverse aspects of nervous system development and plasticity, ranging from axon guidance and neuron migration to synaptic organization. PlxnA signaling requires cytoplasmic domain dimerization, but extracellular regulation and activation mechanisms remain unclear. Here we present crystal structures of PlxnA (PlxnA1, PlxnA2, and PlxnA4) full ectodomains. Domains 1-9 form a ring-like conformation from which the C-terminal domain 10 points away...
August 3, 2016: Neuron
Francesc Perez-Branguli, Yvrick Zagar, Daniel K Shanley, Isabella A Graef, Alain Chédotal, Kevin J Mitchell
The transmembrane semaphorin, Sema6A, has important roles in axon guidance, cell migration and neuronal connectivity in multiple regions of the nervous system, mediated by context-dependent interactions with plexin receptors, PlxnA2 and PlxnA4. Here, we demonstrate that Sema6A can also signal cell-autonomously, in two modes, constitutively, or in response to higher-order clustering mediated by either PlxnA2-binding or chemically induced multimerisation. Sema6A activation stimulates recruitment of Abl to the cytoplasmic domain of Sema6A and phos¡phorylation of this cytoplasmic tyrosine kinase, as well as phosphorylation of additional cytoskeletal regulators...
2016: PloS One
Silvia S Kang, Aishe Kurti, Aleksandra Wojtas, Kelsey E Baker, Chia-Chen Liu, Takahisa Kanekiyo, Yuetiva Deming, Carlos Cruchaga, Steven Estus, Guojun Bu, John D Fryer
Although abundant genetic and biochemical evidence strongly links Clusterin (CLU) to Alzheimer disease (AD) pathogenesis, the receptor for CLU within the adult brain is currently unknown. Using unbiased approaches, we identified Plexin A4 (PLXNA4) as a novel, high-affinity receptor for CLU in the adult brain. PLXNA4 protein expression was highest in brain with much lower levels in peripheral organs. CLU protein levels were significantly elevated in the cerebrospinal fluid (CSF) of Plxna4(-/-) mice and, in humans, CSF levels of CLU were also associated with PLXNA4 genotype...
July 4, 2016: Human Molecular Genetics
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