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Amanda Phuong Tran, Sapna Sundar, Meigen Yu, Bradley T Lang, Jerry Silver
Severed axon tips reform growth cones following spinal cord injury that fail to regenerate, in part, because they become embedded within an inhibitory extracellular matrix. Chondroitin sulfate proteoglycans (CSPGs) are the major axon inhibitory matrix component that is increased within the lesion scar and in perineuronal nets around deafferented neurons. We have recently developed a novel peptide modulator (Intracellular Sigma Peptide or ISP) of the cognate receptor of CSPGs, protein tyrosine phosphatase sigma (RPTPσ), which has been shown to markedly improve sensorimotor function, micturition, and coordinated locomotor behavior in spinal cord contused rats...
May 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Yotis A Senis, Alastair J Barr
Protein tyrosine phosphatases (PTPs), of the receptor and non-receptor classes, are key signaling molecules that play critical roles in cellular regulation underlying diverse physiological events. Aberrant signaling as a result of genetic mutation or altered expression levels has been associated with several diseases and treatment via pharmacological intervention at the level of PTPs has been widely explored; however, the challenges associated with development of small molecule phosphatase inhibitors targeting the intracellular phosphatase domain (the "inside-out" approach) have been well documented and as yet there are no clinically approved drugs targeting these enzymes...
March 2, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Kouki Tadai, Tatsumasa Shioiri, Jun Tsuchimoto, Naoko Nagai, Hideto Watanabe, Nobuo Sugiura
Receptor type of protein tyrosine phosphatase sigma (RPTPσ) functions as a glycosaminoglycan (GAG) receptor of neuronal cells in both the central and peripheral nervous systems. Both chondroitin sulfate (CS) and heparan sulfate (HS) are important constituents of GAG ligands for RPTPσ, although they have opposite effects on neuronal cells. CS inhibits neurite outgrowth and neural regeneration through RPTPσ, whereas HS enhances them. We prepared recombinant RPTPσ N-terminal fragment containing the GAG binding site and various types of biotin-conjugated GAG (CS and HS) with chemical modification and chemo-enzymatic synthesis...
February 6, 2018: Journal of Biochemistry
Adam R Griffith, Claude J Rogers, Gregory M Miller, Ravinder Abrol, Linda C Hsieh-Wilson, William A Goddard
Cell-surface carbohydrates play important roles in numerous biological processes through their interactions with various protein-binding partners. These interactions are made possible by the vast structural diversity of carbohydrates and the diverse array of carbohydrate presentations on the cell surface. Among the most complex and important carbohydrates are glycosaminoglycans (GAGs), which display varied stereochemistry, chain lengths, and patterns of sulfation. GAG-protein interactions participate in neuronal development, angiogenesis, spinal cord injury, viral invasion, and immune response...
December 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
Katherine Stewart, You Chi Tang, Maxwell E R Shafer, Adda-Lee Graham-Paquin, Maxime Bouchard
The elimination of unwanted cells by apoptosis is necessary for tissue morphogenesis. However, the cellular control of morphogenetic apoptosis is poorly understood, notably the modulation of cell sensitivity to apoptotic stimuli. Ureter maturation, the process by which the ureter is displaced to the bladder wall, represents an exquisite example of morphogenetic apoptosis, requiring the receptor protein tyrosine phosphatases (RPTPs): LAR and RPTPσ. Here we show that LAR-RPTPs act through cellular inhibitor of apoptosis protein 1 (cIAP1) to modulate caspase 3,7-mediated ureter maturation...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
Chia-Lun Wu, Serge Hardy, Isabelle Aubry, Melissa Landry, Allison Haggarty, Horacio Uri Saragovi, Michel L Tremblay
Receptor tyrosine phosphatase sigma (RPTPσ) plays an important role in the regulation of axonal outgrowth and neural regeneration. Recent studies have identified two RPTPσ ligands, chondroitin sulfate proteoglycans (CSPGs) and heparan sulfate proteoglycans (HSPG), which can modulate RPTPσ activity by affecting its dimerization status. Here, we developed a split luciferase assay to monitor RPTPσ dimerization in living cells. Using this system, we demonstrate that heparin, an analog of heparan sulfate, induced the dimerization of RPTPσ, whereas chondroitin sulfate increased RPTPσ activity by inhibiting RPTPσ dimerization...
2017: PloS One
Karen M Doody, Stephanie M Stanford, Cristiano Sacchetti, Mattias N D Svensson, Charlotte H Coles, Nikolaos Mitakidis, William B Kiosses, Beatrix Bartok, Camille Fos, Esther Cory, Robert L Sah, Ru Liu-Bryan, David L Boyle, Heather A Arnett, Tomas Mustelin, Maripat Corr, Jeffrey D Esko, Michel L Tremblay, Gary S Firestein, A Radu Aricescu, Nunzio Bottini
Despite the availability of several therapies for rheumatoid arthritis (RA) that target the immune system, a large number of RA patients fail to achieve remission. Joint-lining cells, called fibroblast-like synoviocytes (FLS), become activated during RA and mediate joint inflammation and destruction of cartilage and bone. We identify RPTPσ, a transmembrane tyrosine phosphatase, as a therapeutic target for FLS-directed therapy. RPTPσ is reciprocally regulated by interactions with chondroitin sulfate or heparan sulfate containing extracellular proteoglycans in a mechanism called the proteoglycan switch...
May 20, 2015: Science Translational Medicine
Scott M Dyck, Arsalan Alizadeh, Kallivalappil T Santhosh, Evan H Proulx, Chia-Lun Wu, Soheila Karimi-Abdolrezaee
Multipotent adult neural precursor cells (NPCs) have tremendous intrinsic potential to repair the damaged spinal cord. However, evidence shows that the regenerative capabilities of endogenous and transplanted NPCs are limited in the microenvironment of spinal cord injury (SCI). We previously demonstrated that injury-induced upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) restricts the survival, migration, integration, and differentiation of NPCs following SCI. CSPGs are long-lasting components of the astroglial scar that are formed around the lesion...
August 2015: Stem Cells
Charlotte H Coles, Nikolaos Mitakidis, Peng Zhang, Jonathan Elegheert, Weixian Lu, Andrew W Stoker, Terunaga Nakagawa, Ann Marie Craig, E Yvonne Jones, A Radu Aricescu
Receptor protein tyrosine phosphatase sigma (RPTPσ) regulates neuronal extension and acts as a presynaptic nexus for multiple protein and proteoglycan interactions during synaptogenesis. Unknown mechanisms govern the shift in RPTPσ function, from outgrowth promotion to synaptic organization. Here, we report crystallographic, electron microscopic and small-angle X-ray scattering analyses, which reveal sufficient inter-domain flexibility in the RPTPσ extracellular region for interaction with both cis (same cell) and trans (opposite cell) ligands...
November 11, 2014: Nature Communications
Heng-Xing Zhou, Xue-Ying Li, Fu-Yuan Li, Chang Liu, Zhi-Pin Liang, Shen Liu, Bin Zhang, Tian-Yi Wang, Tian-Ci Chu, Lu Lu, Guang-Zhi Ning, Xiao-Hong Kong, Shi-Qing Feng
After spinal cord injury (SCI), the rapidly upregulated chondroitin sulfate proteoglycans (CSPGs), the prominent chemical constituents and main repulsive factors of the glial scar, play an important role in the extremely limited ability to regenerate in adult mammals. Although many methods to overcome the inhibition have been tested, no successful method with clinical feasibility has been devised to date. It was recently discovered that receptor protein tyrosine phosphatase sigma (RPTPσ) is a functional receptor for CSPGs-mediated inhibition...
October 24, 2014: Brain Research
Jae-Hyuk Yi, Yasuhiro Katagiri, Panpan Yu, Jacob Lourie, Nathanael J Bangayan, Aviva J Symes, Herbert M Geller
The role of type IIA receptor protein tyrosine phosphatases (RPTPs), which includes LAR, RPTPσ and RPTPδ, in the nervous system is becoming increasingly recognized. Evidence supports a significant role for these RPTPs during the development of the nervous system as well as after injury, and mutations in RPTPs are associated with human disease. However, a major open question is the nature of the ligands that interact with type IIA RPTPs in the adult brain. Candidates include several different proteins as well as the glycosaminoglycan chains of proteoglycans...
May 2014: Experimental Neurology
Katherine Stewart, Noriko Uetani, Wiljan Hendriks, Michel L Tremblay, Maxime Bouchard
Leukocyte antigen related (LAR) family receptor protein tyrosine phosphatases (RPTPs) regulate the fine balance between tyrosine phosphorylation and dephosphorylation that is crucial for cell signaling during development and tissue homeostasis. Here we show that LAR RPTPs are required for normal development of the mandibular and maxillary regions. Approximately half of the mouse embryos lacking both Ptprs (RPTPσ) and Ptprf (LAR) exhibit micrognathia (small lower jaw), cleft palate and microglossia/glossoptosis (small and deep tongue), a phenotype closely resembling Pierre-Robin sequence in humans...
August 2013: Development
Katherine E Horn, Bin Xu, Delphine Gobert, Bassam N Hamam, Katherine M Thompson, Chia-Lun Wu, Jean-François Bouchard, Noriko Uetani, Ronald J Racine, Michel L Tremblay, Edward S Ruthazer, C Andrew Chapman, Timothy E Kennedy
The mechanisms that regulate synapse formation and maintenance are incompletely understood. In particular, relatively few inhibitors of synapse formation have been identified. Receptor protein tyrosine phosphatase σ (RPTPσ), a transmembrane tyrosine phosphatase, is widely expressed by neurons in developing and mature mammalian brain, and functions as a receptor for chondroitin sulfate proteoglycans that inhibits axon regeneration following injury. In this study, we address RPTPσ function in the mature brain...
July 2012: Journal of Neurochemistry
Travis L Dickendesher, Katherine T Baldwin, Yevgeniya A Mironova, Yoshiki Koriyama, Stephen J Raiker, Kim L Askew, Andrew Wood, Cédric G Geoffroy, Binhai Zheng, Claire D Liepmann, Yasuhiro Katagiri, Larry I Benowitz, Herbert M Geller, Roman J Giger
In the adult mammalian CNS, chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors (MAIs) stabilize neuronal structure and restrict compensatory sprouting following injury. The Nogo receptor family members NgR1 and NgR2 bind to MAIs and have been implicated in neuronal inhibition. We found that NgR1 and NgR3 bind with high affinity to the glycosaminoglycan moiety of proteoglycans and participate in CSPG inhibition in cultured neurons. Nogo receptor triple mutants (Ngr1(-/-); Ngr2(-/-); Ngr3(-/-); which are also known as Rtn4r, Rtn4rl2 and Rtn4rl1, respectively), but not single mutants, showed enhanced axonal regeneration following retro-orbital optic nerve crush injury...
March 11, 2012: Nature Neuroscience
Charlotte H Coles, Yingjie Shen, Alan P Tenney, Christian Siebold, Geoffrey C Sutton, Weixian Lu, John T Gallagher, E Yvonne Jones, John G Flanagan, A Radu Aricescu
Heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) regulate numerous cell surface signaling events, with typically opposite effects on cell function. CSPGs inhibit nerve regeneration through receptor protein tyrosine phosphatase sigma (RPTPσ). Here we report that RPTPσ acts bimodally in sensory neuron extension, mediating CSPG inhibition and HSPG growth promotion. Crystallographic analyses of a shared HSPG-CSPG binding site reveal a conformational plasticity that can accommodate diverse glycosaminoglycans with comparable affinities...
April 22, 2011: Science
Catherine A Boucher, Heather H Ward, Ruth L Case, Katie S Thurston, Xiaohong Li, Andrew Needham, Elsa Romero, Deborah Hyink, Seema Qamar, Tamara Roitbak, Samantha Powell, Christopher Ward, Patricia D Wilson, Angela Wandinger-Ness, Richard N Sandford
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutation of PKD1 and PKD2 that encode polycystin-1 and polycystin-2. Polycystin-1 is tyrosine phosphorylated and modulates multiple signaling pathways including AP-1, and the identity of the phosphatases regulating polycystin-1 are previously uncharacterized. Here we identify members of the LAR protein tyrosine phosphatase (RPTP) superfamily as members of the polycystin-1complex mediated through extra- and intracellular interactions. The first extracellular PKD1 domain of polycystin-1 interacts with the first Ig domain of RPTPσ, while the polycystin-1 C-terminus of polycystin-1 interacts with the regulatory D2 phosphatase domain of RPTPγ...
October 2011: Biochimica et Biophysica Acta
Mélanie J Chagnon, Chia-Lun Wu, Takanobu Nakazawa, Tadashi Yamamoto, Masaharu Noda, Christophe Blanchetot, Michel L Tremblay
Cumulative evidence supports an important role for RPTPsigma in the development of the nervous system and nerve regeneration. However, the signaling mechanisms regulated by RPTPsigma remain largely unknown and the identification of RPTPsigma substrate(s) and binding partners is essential to understanding its mechanisms of action. We employed a modified yeast-two-hybrid approach, the yeast substrate-trapping system, to identify new substrates and interacting partners of RPTPsigma. The binding proteins RPTPdelta, Liprinalpha4, p130Cas and Trio were found to interact with RPTPsigma in the yeast system independently of tyrosine phosphorylation...
November 2010: Cellular Signalling
Jacqueline Reinhard, Andrea Horvat-Bröcker, Sebastian Illes, Angelika Zaremba, Piotr Knyazev, Axel Ullrich, Andreas Faissner
Protein tyrosine phosphatases (PTPs) are key regulators of different processes during development of the central nervous system. However, expression patterns and potential roles of PTPs in the developing superior colliculus remain poorly investigated. In this study, a degenerate primer-based reverse transcription-polymerase chain reaction (RT-PCR) approach was used to isolate seven different intracellular PTPs and nine different receptor-type PTPs (RPTPs) from embryonic E15 mouse superior colliculus. Subsequently, the expression patterns of 11 PTPs (TC-PTP, PTP1C, PTP1D, PTP-MEG2, PTP-PEST, RPTPJ, RPTPε, RPTPRR, RPTPσ, RPTPκ and RPTPγ) were further analyzed in detail in superior colliculus from embryonic E13 to postnatal P20 stages by quantitative real-time RT-PCR, Western blotting and immunohistochemistry...
December 2009: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
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