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slit robo gap

Sokjoong Chung, Seungsoo Rho, Gijin Kim, So-Ra Kim, Kwang-Hyun Baek, Myungseo Kang, Helen Lew
The use of mesenchymal stem cells (MSCs) in cell therapy in regenerative medicine has great potential, particularly in the treatment of nerve injury. Umbilical cord blood (UCB) reportedly contains stem cells, which have been widely used as a hematopoietic source and may have therapeutic potential for neurological impairment. Although ongoing research is dedicated to the management of traumatic optic nerve injury using various measures, novel therapeutic strategies based on the complex underlying mechanisms responsible for optic nerve injury, such as inflammation and/or ischemia, are required...
May 2016: International Journal of Molecular Medicine
Min Li, Chao Quan, Rachel Toth, David G Campbell, Carol MacKintosh, Hong Yu Wang, Shuai Chen
Diabetes is strongly associated with cognitive decline, but the molecular reasons are unknown. We found that fasting and peripheral insulin promote phosphorylation and dephosphorylation, respectively, of specific residues on brain proteins including cytoskeletal regulators such as slit-robo GTPase-activating protein 3 (srGAP3) and microtubule affinity-regulating protein kinases (MARKs), in which deficiency or dysregulation is linked to neurological disorders. Fasting activates protein kinase A (PKA) but not PKB/Akt signaling in the brain, and PKA can phosphorylate the purified srGAP3...
December 11, 2015: Journal of Biological Chemistry
Xiao-Tong Li, Qi-Sheng Zhou, Qi Yu, Xiao Zhao, Qing-Xin Liu
The axon guidance molecule Robo is a transmembrane protein which is conserved during evolution. Robo and its ligand, Slit, have been implicated in regulating many developmental processes, such as axon guidance, neuronal migration, tumor metastasis, angiogenesis, lung morphogenesis, kidney morphogenesis, heart morphogenesis, ovary development and gonad development. Robo function mainly depends on the binding of its Ig1 domain to the LRR-2 domain of Slit ligand. Meanwhile, Robo function is also mediated by binding to some signaling molecules, including the heparan sulfate proteoglycans (HSPGs), GTPase-activating proteins (GAPs) and tyrosine kinase Abelson...
June 25, 2014: Sheng Li Xue Bao: [Acta Physiologica Sinica]
Yun-Kai Dai, Yue Ma, Keng Chen, Ya-Jing Mi, Hua-Lin Fu, Da-Xiang Cui, Wei-Lin Jin
The Slit-Robo GTPase activating protein 3 (srGAP3) is an important modulator of actin cytoskeletal dynamics and has an important influence on a variety of neurodevelopmental processes. Mutations in the SRGAP3 gene on chromosome 3p25 have been found in patients with intellectual disability. Genome-wide association studies and behavioral assays of knockout mice had also revealed SRGAP3 as a risk gene for schizophrenia. We have recently shown that srGAP3 protein undergoes regulated shuttling between the cytoplasm and the nucleus during neuronal development...
May 2014: Molecular and Cellular Neurosciences
Daisuke Yamazaki, Toshiki Itoh, Hiroaki Miki, Tadaomi Takenawa
The distinct levels of Rac activity differentially regulate the pattern of intrinsic cell migration. However, it remains unknown how Rac activity is modulated and how the level of Rac activity controls cell migratory behavior. Here we show that Slit-Robo GAP 1 (srGAP1) is a modulator of Rac activity in locomotive cells. srGAP1 possesses a GAP activity specific to Rac1 and is recruited to lamellipodia in a Rac1-dependent manner. srGAP1 limits Rac1 activity and allows concomitant activation of Rac1 and RhoA, which are mutually inhibitory...
November 2013: Molecular Biology of the Cell
A Lahoz, A Hall
srGAP3, a member of the Slit-Robo sub-family of Rho GTPase-activating proteins (Rho GAPs), controls actin and microtubule dynamics through negative regulation of Rac. Here, we describe a potential role for srGAP3 as a tumor suppressor in mammary epithelial cells. We show that RNAi-mediated depletion of srGAP3 promotes Rac dependent, anchorage-independent growth of partially transformed human mammary epithelial cells (HMECs). Furthermore, srGAP3 expression is absent, or significantly reduced in 7/10 breast cancer cell lines compared with normal HMECs...
October 2013: Oncogene
Timothy Loveless, Jeff Hardin
Cadherin superfamily proteins mediate cell-cell adhesion during development. The C. elegans embryo is a powerful system for analyzing how cadherins function in highly stereotyped morphogenetic events. In the embryo, the classical cadherin HMR-1 acts along with the Rac pathway and SAX-7/L1CAM during gastrulation. As adherens junctions mature, PAR complex proteins differentially regulate cadherin complex localization, and SRGP-1/Slit/Robo GAP aids adhesion by promoting membrane bending. Once adherens junctions form, actin is linked to the cell surface via HMP-1/α-catenin, whose actin binding activity is regulated in novel ways...
October 2012: Current Opinion in Cell Biology
Qi Yu, Qi-Sheng Zhou, Xiao Zhao, Qing-Xin Liu
The axon guidance molecule Slit is a secreted glucoprotein which is conserved during evolution. Slit has been implicated in regulating a variety of life activities, such as axon guidance, neuronal migration, neuronal morphological differentiation, tumor metastasis, angiogenesis and heart morphogenesis. Slit function mainly depends on the binding of its LRR-2 domain to the Ig1 domain of Roundabout (Robo) receptor, meanwhile Slit function is also mediated by a range of signaling molecules, including the heparan sulfate proteoglycans (HSPGs), GTPase-activating proteins (GAPs), tyrosine kinase Abelson, calcium ions, MicroRNA-218 and other axon guidance molecules...
April 25, 2012: Sheng Li Xue Bao: [Acta Physiologica Sinica]
Volker Endris, Lydia Haussmann, Elena Buss, Claire Bacon, Dusan Bartsch, Gudrun Rappold
SrGAP3/MEGAP is a member of the Slit-Robo GAP (srGAP) family and is implicated in repulsive axon guidance and neuronal migration through Slit-Robo-mediated signal transduction. Here we describe an inhibitory role of srGAP3 on actin dynamics, specifically on lamellipodia formation. We show that the F-BAR domain localizes srGAP3 to the leading edge of cellular protrusions whereas the SH3 domain is important for focal adhesion targeting. We report on a novel srGAP3 interaction partner, lamellipodin, which localizes with srGAP3 at the leading edge...
December 1, 2011: Journal of Cell Science
Christopher A Jones, Naoyuki Nishiya, Nyall R London, Weiquan Zhu, Lise K Sorensen, Aubrey C Chan, Chinten J Lim, Haoyu Chen, Qisheng Zhang, Peter G Schultz, Alaa M Hayallah, Kirk R Thomas, Michael Famulok, Kang Zhang, Mark H Ginsberg, Dean Y Li
Slit-Roundabout (Robo) signalling has a well-understood role in axon guidance. Unlike in the nervous system, however, Slit-dependent activation of an endothelial-specific Robo, Robo4, does not initiate a guidance program. Instead, Robo4 maintains the barrier function of the mature vascular network by inhibiting neovascular tuft formation and endothelial hyperpermeability induced by pro-angiogenic factors. In this study, we used cell biological and biochemical techniques to elucidate the molecular mechanism underlying the maintenance of vascular stability by Robo4...
November 2009: Nature Cell Biology
Barry J Dickson, Giorgio F Gilestro
Commissural axons grow along complex pathways toward, across, and beyond the midline of the central nervous system. Taking commissural axons in the vertebrate spinal cord and the Drosophila ventral nerve cord as examples, we examine how commissural axon pathfinding is regulated by the Slit family of guidance cues and their Robo family receptors. We extract several principles that seem likely to apply to other axons and other contexts, such as the reiterative use of the same guidance molecules in distinct pathfinding decisions, the transcriptional specification of a pathway, the posttranscriptional regulation of growth along the pathway, and the possible role of feedback mechanisms to ensure the fidelity of pathfinding choices...
2006: Annual Review of Cell and Developmental Biology
Xiaofeng Li, Yushu Chen, Yiwei Liu, Jia Gao, Feng Gao, Mark Bartlam, Jane Y Wu, Zihe Rao
The Slit-Robo (sr) GTPase-activating protein (GAPs) are important components in the intracellular pathway mediating Slit-Robo signaling in axon guidance and cell migration. We report the first crystal structure of the srGAP1 SH3 domain at 1.8-A resolution. The unusual side chain conformation of the conserved Phe-13 in the P1 pocket renders the ligand binding pocket shallow and narrow, which contributes toward the low binding affinity. Moreover, the opposing electrostatic charge and the hydrophobic properties of the P3 specificity pocket are consistent with the observed binding characteristics of the srGAP1 SH3 domain to its ligand...
September 22, 2006: Journal of Biological Chemistry
Tianbo Ren, Aurora Anderson, Wei-Bin Shen, Hao Huang, Celine Plachez, Jiangyang Zhang, Susumu Mori, Stephen L Kinsman, Linda J Richards
A complex set of axonal guidance mechanisms are utilized by axons to locate and innervate their targets. In the developing mouse forebrain, we previously described several midline glial populations as well as various guidance molecules that regulate the formation of the corpus callosum. Since agenesis of the corpus callosum is associated with over 50 different human congenital syndromes, we wanted to investigate whether these same mechanisms also operate during human callosal development. Here we analyze midline glial and commissural development in human fetal brains ranging from 13 to 20 weeks of gestation using both diffusion tensor magnetic resonance imaging and immunohistochemistry...
February 2006: Anatomical Record. Part A, Discoveries in Molecular, Cellular, and Evolutionary Biology
Annika Lundström, Marco Gallio, Camilla Englund, Pär Steneberg, Johanna Hemphälä, Pontus Aspenström, Krystyna Keleman, Ludmilla Falileeva, Barry J Dickson, Christos Samakovlis
Slit proteins steer the migration of many cell types through their binding to Robo receptors, but how Robo controls cell motility is not clear. We describe the functional analysis of vilse, a Drosophila gene required for Robo repulsion in epithelial cells and axons. Vilse defines a conserved family of RhoGAPs (Rho GTPase-activating proteins), with representatives in flies and vertebrates. The phenotypes of vilse mutants resemble the tracheal and axonal phenotypes of Slit and Robo mutants at the CNS midline...
September 1, 2004: Genes & Development
Tomas Madura, Toshihide Yamashita, Tateki Kubo, Lyuji Tsuji, Ko Hosokawa, Masaya Tohyama
Complex processes following peripheral nerve injury integrate a number of various external cues and their intracellular responses resulting in the cytoskeletal remodeling. One of these cues, Slit protein, plays an important role in neuronal migration and axonal guidance through the interaction with Roundabout (Robo) receptor. It was reported that the signal from Robo is transmitted to a specific family of GTPase-activating proteins (GAPs) named Slit-Robo GAPs. The Slit-Robo GAPs (srGAPs) further transmit the signal to the actin cytoskeleton controlling Rho GTPases and thus provide a direct link between Slit-Robo signaling and actin cytoskeleton...
April 7, 2004: Brain Research. Molecular Brain Research
Volker Endris, Birgit Wogatzky, Uwe Leimer, Dusan Bartsch, Malgorzata Zatyka, Farida Latif, Eamonn R Maher, Gholamali Tariverdian, Stefan Kirsch, Dieter Karch, Gudrun A Rappold
In the last few years, several genes involved in X-specific mental retardation (MR) have been identified by using genetic analysis. Although it is likely that additional genes responsible for idiopathic MR are also localized on the autosomes, cloning and characterization of such genes have been elusive so far. Here, we report the isolation of a previously uncharacterized gene, MEGAP, which is disrupted and functionally inactivated by a translocation breakpoint in a patient who shares some characteristic clinical features, such as hypotonia and severe MR, with the 3p(-) syndrome...
September 3, 2002: Proceedings of the National Academy of Sciences of the United States of America
Aurnab Ghose, David Van Vactor
Neuronal migration requires the integration of a number of diverse environmental cues and subsequent translation to specific responses such as directed cytoskeletal remodeling. Accurate knowledge of the signal transduction pathways linking activation of surface receptors to actin dynamics is necessary in order to understand the regulation of such processes. Activation of the Roundabout (Robo) receptor mediates a repulsive response in certain pioneering axons and migratory neurons. Recently, Wong et al have described a signaling link between Robo activation and specific GTPase activity that appears to regulate neuronal migration...
May 2002: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
K Wong, X R Ren, Y Z Huang, Y Xie, G Liu, H Saito, H Tang, L Wen, S M Brady-Kalnay, L Mei, J Y Wu, W C Xiong, Y Rao
The Slit protein guides neuronal and leukocyte migration through the transmembrane receptor Roundabout (Robo). We report here that the intracellular domain of Robo interacts with a novel family of Rho GTPase activating proteins (GAPs). Two of the Slit-Robo GAPs (srGAPs) are expressed in regions responsive to Slit. Slit increased srGAP1-Robo1 interaction and inactivated Cdc42. A dominant negative srGAP1 blocked Slit inactivation of Cdc42 and Slit repulsion of migratory cells from the anterior subventricular zone (SVZa) of the forebrain...
October 19, 2001: Cell
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