PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

Ko, Ji Seung; Pramanik, Gopal; Um, Ji Won; Shim, Ji Seon; Lee, Dongmin; Kim, Kee Hun; Chung, Gug-Young; Condomitti, Giuseppe; Kim, Ho Min; Kim, Hyun; Wit, Joris de; Park, Kang-Sik; Tabuchi, Katsuhiko; Ko, Jaewon

doi:10.1073/pnas.1410138112

Cited by 94 publications

(92 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It may relate to diversity in the ligands and substrates of RPTPs, indirect links along the different intracellular pathways and multiple interactions among the signals. Although CSPGs and Although HSPGs appear to be the substrates of PTPσ and LAR15168485, the physical ligands of these receptors are incompletely identified. N-cadherin, β-catenin, and p250GAP are the reported substrates of RPTPs86, but PTPσ and LAR may have other unidentified substrates.…”

Section: Discussionmentioning

confidence: 99%

Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons

Ohtake

Wong

Abdul-Muneer

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member LAR act as transmembrane receptors that mediate growth inhibition of chondroitin sulfate proteoglycans (CSPGs). Inhibition of either receptor increases axon growth into and beyond scar tissues after CNS injury. However, it is unclear why neurons express two similar CSPG receptors, nor whether they use the same or different intracellular pathways. We have now studied the signaling pathways of these two receptors using N2A cells and primary neurons derived from knockout mice. We demonstrate that both receptors share certain signaling pathways (RhoA, Akt and Erk), but also use distinct signals to mediate CSPG actions. Activation of PTPσ by CSPGs selectively inactivated CRMP2, APC, S6 kinase and CREB. By contrast LAR activation inactivated PKCζ, cofilin and LKB1. For the first time, we propose a model of the signaling pathways downstream of these two CSPG receptors. We also demonstrate that deleting both receptors exhibits additive enhancement of axon growth in adult neuronal cultures in vitro. Our findings elucidate the novel downstream pathways of CSPGs and suggest potential synergy of blocking their two PTP receptors.

show abstract

Section: Discussionmentioning

confidence: 99%

Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons

Ohtake

Wong

Abdul-Muneer

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…LRRTM1-3 bind to α- and β-neurexins with high affinity, but only when these neurexins lack an insert in SS4 (Ko et al, 2009a; de Wit et al, 2009; Siddique et al, 2010; Um et al, 2016). LRRTM4 binds to glypicans via their heparan sulfate proteoglycan modification, and may also bind to neurexins (Siddiqui et al, 2013; de Wit et al, 2013; Ko et al, 2015). LRRTM4 was additionally identified as a stoichiometric component of AMPAR complexes, and other LRRTMs probably also bind to AMPARs (Schwenk et al, 2012).…”

Section: Lrrtmsmentioning

confidence: 99%

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

Südhof

2017

Cell

663

718

View full text Add to dashboard Cite

Synapses are specialized junctions between neurons in brain that transmit and compute information, thereby connecting neurons into millions of overlapping and interdigitated neural circuits. Here we posit that the establishment, properties, and dynamics of synapses are governed by a molecular logic that is controlled by diverse trans-synaptic signaling molecules. Neurexins, expressed in thousands of alternatively spliced isoforms, are central components of this dynamic code. Presynaptic neurexins regulate synapse properties via differential binding to multifarious postsynaptic ligands, such as neuroligins, cerebellin/GluD complexes, and latrophilins, thereby shaping the input/output relations of their resident neural circuits. Mutations in genes encoding neurexins and their ligands are associated with diverse neuropsychiatric disorders, especially schizophrenia, autism, and Tourette syndrome. Thus, neurexins nucleate an overall trans-synaptic signaling network that controls synapse properties, that thereby determines the precise responses of synapses to spike patterns in a neuron and circuit, and that is vulnerable to impairments in neuropsychiatric disorders.

show abstract

“…Presynaptic Gpc4 also functions as a cell-adhesion receptor for post-synaptic LRRTM4, thereby regulating the number of excitatory synaptic connections (de Wit et al, 2013). The HS chains of Gpc4 and Gpc6 play an essential role in synaptogenesis (Allen et al, 2012; Ko et al, 2015). Sdc2, a transmembrane HSPG, is required for maturation of dendritic spines in hippocampal neurons (Ethell and Yamaguchi, 1999).…”

Section: Heparan Sulfate and Heparan Sulfate Proteoglycansmentioning

confidence: 99%

Glycan susceptibility factors in autism spectrum disorders

Dwyer

2016

Molecular Aspects of Medicine

View full text Add to dashboard Cite

Idiopathic autism spectrum disorders (ASDs) are neurodevelopmental disorders with unknown etiology. An estimated 1:68 children in the U.S. are diagnosed with ASDs, making these disorders a substantial public health issue. Recent advances in genome sequencing have identified numerous genetic variants across the ASD patient population. Many genetic variants identified occur in genes that encode glycosylated extracellular proteins (proteoglycans or glycoproteins) or enzymes involved in glycosylation (glycosyltransferases and sulfotransferases). It remains unknown whether “glycogene” variants cause changes in glycosylation and whether they contribute to the etiology and pathogenesis of ASDs. Insights into glycan susceptibility factors are provided by studies in the normal brain and congenital disorders of glycosylation, which are often accompanied by ASD-like behaviors. The purpose of this review is to present evidence that supports a contribution of extracellular glycans and glycoconjugates to the etiology and pathogenesis of idiopathic ASDs and other types of pervasive neurodevelopmental disorders.

show abstract

PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

Cited by 94 publications

References 45 publications

Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons

Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

Glycan susceptibility factors in autism spectrum disorders

Contact Info

Product

Resources

About