Cell surface nucleolin on developing muscle is a potential ligand for the axonal receptor protein tyrosine phosphatase‐σ

Alete, Daniel E.; Weeks, Mark E.; Hovanession, Ara G.; Hawadle, Muhamed; Stoker, Andrew W.

doi:10.1111/j.1742-4658.2006.05471.x

Cited by 31 publications

(18 citation statements)

References 74 publications

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“…A significant amount of NCL was also found on the cell surface of developing muscle and growing cells (43,67). Hence, the ubiquitous expression and tissue distribution of NCL not only indicate that NCL is involved in EV71 infections but also suggest that the binding of EV71 to cells of the mononuclear phagocyte system, growing cells, and developing muscle is more efficient than its binding to other cells.…”

Section: Discussionmentioning

confidence: 85%

Cell Surface Nucleolin Facilitates Enterovirus 71 Binding and Infection

Wang

Huang

et al. 2015

J Virol

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Because the pathogenesis of enterovirus 71 (EV71) remains mostly ambiguous, identifying the factors that mediate viral binding and entry to host cells is indispensable to ultimately uncover the mechanisms that underlie virus infection and pathogenesis. Despite the identification of several receptors/attachment molecules for EV71, the binding, entry, and infection mechanisms of EV71 remain unclear. Herein, we employed glycoproteomic approaches to identify human nucleolin as a novel binding receptor for EV71. Glycoproteins purified by lectin chromatography from the membrane extraction of human cells were treated with sialidase, followed by immunoprecipitation with EV71 particles. Among the 16 proteins identified by tandem mass spectrometry analysis, cell surface nucleolin attracted our attention. We found that EV71 interacted directly with nucleolin via the VP1 capsid protein and that an antinucleolin antibody reduced the binding of EV71 to human cells. In addition, the knockdown of cell surface nucleolin decreased EV71 binding, infection, and production in human cells. Furthermore, the expression of human nucleolin on the cell surface of a mouse cell line increased EV71 binding and conferred EV71 infection and production in the cells. These results strongly indicate that human nucleolin can mediate EV71 binding to and infection of cells. Our findings also demonstrate that the use of glycoproteomic approaches is a reliable methodology to discover novel receptors for pathogens. IMPORTANCEOutbreaks of EV71 have been reported in Asia-Pacific countries and have caused thousands of deaths in young children during the last 2 decades. The discovery of new EV71-interacting molecules to understand the infection mechanism has become an emergent issue. Hence, this study uses glycoproteomic approaches to comprehensively investigate the EV71-interacting glycoproteins. Several EV71-interacting glycoproteins are identified, and the role of cell surface nucleolin in mediating the attachment and entry of EV71 is characterized and validated. Our findings not only indicate a novel target for uncovering the EV71 infection mechanism and anti-EV71 drug discovery but also provide a new strategy for virus receptor identification.

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Section: Discussionmentioning

confidence: 85%

Cell Surface Nucleolin Facilitates Enterovirus 71 Binding and Infection

Wang

Huang

et al. 2015

J Virol

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“…PTP interacts with two heparan sulfate proteoglycans, agrin and collagen XVIII, through the first Ig domain (53) and with ␣-latrotoxin of black widow spider venom through the FNIII 2-3 domains (54). Nucleolin, a protein detected on the surface of developing myotubes, has been suggested to bind PTP (55). More recently, the first Ig domain of PTP was shown to bind chondroitin sulfate proteoglycans, which are produced by cell types, including reactive astroglia at sites of neuronal injury for the inhibition of axonal regeneration (56).…”

Section: Discussionmentioning

confidence: 99%

Trans-synaptic Adhesions between Netrin-G Ligand-3 (NGL-3) and Receptor Tyrosine Phosphatases LAR, Protein-tyrosine Phosphatase δ (PTPδ), and PTPσ via Specific Domains Regulate Excitatory Synapse Formation

Kwon

Woo

Kim

et al. 2010

Journal of Biological Chemistry

154

172

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Synaptic cell adhesion molecules regulate various steps of synapse formation. The trans-synaptic adhesion between postsynaptic NGL-3 (for netrin-G ligand-3) and presynaptic LAR (for leukocyte antigen-related) regulates excitatory synapse formation in a bidirectional manner. However, little is known about the molecular details of the NGL-3-LAR adhesion and whether two additional LAR family proteins, protein-tyrosine phosphatase ␦ (PTP␦), and PTP, also interact with NGL-3 and are involved in synapse formation. We report here that the leucine-rich repeat (LRR) domain of NGL-3, containing nine LRRs, interacts with the first two fibronectin III (FNIII) domains of LAR to induce bidirectional synapse formation. Moreover, Gln-96 in the first LRR motif of NGL-3 is critical for LAR binding and induction of presynaptic differentiation. PTP␦ and PTP also interact with NGL-3 via their first two FNIII domains. These two interactions promote synapse formation in a different manner; the PTP-NGL-3 interaction promotes synapse formation in a bidirectional manner, whereas the PTP␦-NGL-3 interaction instructs only presynaptic differentiation in a unidirectional manner. mRNAs encoding LAR family proteins display overlapping and differential expression patterns in various brain regions. These results suggest that trans-synaptic adhesion between NGL-3 and the three LAR family proteins regulates excitatory synapse formation in shared and distinct neural circuits.Synaptic cell adhesion molecules have been implicated in the regulation of the initial contacts of dendrites and axons, early synapse formation and maturation, and maintenance and structural plasticity of established synapses (1-16). Recent studies have identified a large number of adhesion molecules that are capable of inducing pre-and postsynaptic differentiation in contacting axons and dendrites, respectively. Examples of such molecules include neuroligins, neurexins, SynCAMs, NGLs (for netrin-G ligand), 3 LAR (for leukocyte antigen-related), LRRTMs, and EphB receptors (17-22).The NGL family of synaptic adhesion molecules contains three known members: NGL-1, NGL-2, and NGL-3 (16, 20, 23). NGL proteins are mainly detected at the postsynaptic site of excitatory synapses (20). NGLs share a common domain structure, comprising nine LRRs and an immunoglobulin (Ig) domain in the extracellular region, followed by a single transmembrane domain and a cytoplasmic region that ends with a PDZ domain-binding motif. The C-terminal PDZ-binding motifs of NGLs bind to the PDZ domains of PSD-95, an abundant postsynaptic scaffolding protein (20). This interaction is thought to couple NGL-dependent trans-synaptic adhesions with postsynaptic differentiation.The extracellular regions of NGLs interact with distinct presynaptic ligands (16). NGL-1 and NGL-2 interact with netrin-G1 and netrin-G2 (also known as laminet-1 and laminet-2), respectively (20, 23), which are glycosylphosphatidylinositol-anchored adhesion molecules (24 -26). NGL-3 interacts with LAR (21), a receptor tyrosine phosphatase that...

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“…Assays of ligand binding to PTP in live cells are not currently available, so we have instead developed a novel RAP strategy to begin to address this question. This assay allowed us to examine the stoichiometry of interactions between soluble PTP-AP fusion proteins and two PTP ligands, the HSPGs (5) and muscle-bound nucleolin (2,45).…”

Section: Ptp Requires Dimerization For Ligand Bindingmentioning

confidence: 99%

“…We monitored the binding of probes to two different ligand types: (i) HSPG ligands in basement membranes (BMs) (5) and (ii) a non-HSPG ligand in skeletal muscle, a component of which is nucleolin (2,45). Proteins FN1d-AP, FN4d-AP, and FN5d-AP had no detectable binding capacity, and FN2d-AP had extremely low activity (Fig.…”

Section: Ptp Requires Dimerization For Ligand Bindingmentioning

confidence: 99%

“…The most significant finding is that PTP binds to these ligands only when it is presented as a dimer. The ligands we have tested include HSPGs and a muscle site that includes nucleolin (2). HSPGs have been shown to modulate PTP interactions with retinal axon receptors (44), and HSPGs have been shown to interact functionally with DLAR, a Drosophila ancestor of PTP, during motor axon guidance and synaptogenesis (19,25).…”

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confidence: 99%

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Dimerization of Protein Tyrosine Phosphatase σ Governs both Ligand Binding and Isoform Specificity

Lee¹,

Faux²,

Nixon³

et al. 2007

Molecular and Cellular Biology

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Signaling through receptor protein tyrosine phosphatases (RPTPs) can influence diverse processes, including axon development, lymphocyte activation, and cell motility. The molecular regulation of these enzymes, however, is still poorly understood. In particular, it is not known if, or how, the dimerization state of RPTPs is related to the binding of extracellular ligands. Protein tyrosine phosphatase (PTP) is an RPTP with major isoforms that differ in their complements of fibronectin type III domains and in their ligand-binding specificities. In this study, we show that PTP forms homodimers in the cell, interacting at least in part through the transmembrane region. Using this knowledge, we provide the first evidence that PTP ectodomains must be presented as dimers in order to bind heterophilic ligands. We also provide evidence of how alternative use of fibronectin type III domain complements in two major isoforms of PTP can alter the ligand binding specificities of PTP ectodomains. The data suggest that the alternative domains function largely to change the rotational conformations of the amino-terminal ligand binding sites of the ectodomain dimers, thus imparting novel ligand binding properties. These findings have important implications for our understanding of how heterophilic ligands interact with, and potentially regulate, RPTPs.Many cell-signaling events are regulated through reversible tyrosine phosphorylation of proteins. This phosphorylation cycle is controlled by the counterbalanced actions of two enzyme families, protein tyrosine kinases and protein tyrosine phosphatases (PTPs), each of which has cytoplasmic and receptorlike members. While the regulation and actions of many receptor protein tyrosine kinases (RTKs) are well characterized, our related understanding of the receptor-type PTPs (RPTPs) remains far from complete.Twenty-one human RPTPs have been identified, and highly conserved orthologues and homologues exist in vertebrates and invertebrates (3). Several of these RPTPs have particularly well-documented roles in neural development (16,26,40), cell adhesion, and motility (7, 51). RPTPs are type I transmembrane proteins with varied extracellular domain structures, and in many cases, it is still unclear what their ligands are. It is also unclear how, and in most cases if, such ligands directly control RPTP activity. Moreover, although RTKs are obligate dimers during ligand activation and signaling, dimerization has been demonstrated for only a small number of RPTPs, and we have only a few clues as to how this dimerization is linked to signaling control. Furthermore, it is not clear whether ligand binding is influenced by, or influences, the RPTP dimerization state.The RPTPs PTP␣, Sap-1, and CD45 form dimers normally in the cell, and this dimerization can block the catalytic action of these enzymes (23,24,64). PTP␣ and CD45 may be inhibited by steric constraints, possibly through an inhibitory wedge structure (8, 29), although this is still controversial (35). With PTP␣ and Sap-1, there is also e...

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Cell surface nucleolin on developing muscle is a potential ligand for the axonal receptor protein tyrosine phosphatase‐σ

Cited by 31 publications

References 74 publications

Cell Surface Nucleolin Facilitates Enterovirus 71 Binding and Infection

Cell Surface Nucleolin Facilitates Enterovirus 71 Binding and Infection

Trans-synaptic Adhesions between Netrin-G Ligand-3 (NGL-3) and Receptor Tyrosine Phosphatases LAR, Protein-tyrosine Phosphatase δ (PTPδ), and PTPσ via Specific Domains Regulate Excitatory Synapse Formation

Dimerization of Protein Tyrosine Phosphatase σ Governs both Ligand Binding and Isoform Specificity

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