Roles in Axon Regeneration and Synaptogenesis
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International Journal of Molecular Sciences Review Type IIa RPTPs and Glycans: Roles in Axon Regeneration and Synaptogenesis Kazuma Sakamoto 1,2 , Tomoya Ozaki 1,2 , Yuji Suzuki 1,2 and Kenji Kadomatsu 1,2,* 1 Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; [email protected] (K.S.); [email protected] (T.O.); [email protected] (Y.S.) 2 Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan * Correspondence: [email protected]; Tel.: +81-52-744-2060 Abstract: Type IIa receptor tyrosine phosphatases (RPTPs) play pivotal roles in neuronal network formation. It is emerging that the interactions of RPTPs with glycans, i.e., chondroitin sulfate (CS) and heparan sulfate (HS), are critical for their functions. We highlight here the significance of these interactions in axon regeneration and synaptogenesis. For example, PTPσ, a member of type IIa RPTPs, on axon terminals is monomerized and activated by the extracellular CS deposited in neural injuries, dephosphorylates cortactin, disrupts autophagy flux, and consequently inhibits axon regeneration. In contrast, HS induces PTPσ oligomerization, suppresses PTPσ phosphatase activity, and promotes axon regeneration. PTPσ also serves as an organizer of excitatory synapses. PTPσ and neurexin bind one another on presynapses and further bind to postsynaptic leucine-rich repeat transmembrane protein 4 (LRRTM4). Neurexin is now known as a heparan sulfate proteoglycan (HSPG), and its HS is essential for the binding between these three molecules. Another HSPG, glypican 4, binds to presynaptic PTPσ and postsynaptic LRRTM4 in an HS-dependent manner. Type Citation: Sakamoto, K.; Ozaki, T.; IIa RPTPs are also involved in the formation of excitatory and inhibitory synapses by heterophilic Suzuki, Y.; Kadomatsu, K. Type IIa binding to a variety of postsynaptic partners. We also discuss the important issue of possible RPTPs and Glycans: Roles in Axon mechanisms coordinating axon extension and synapse formation. Regeneration and Synaptogenesis. Int. J. Mol. Sci. 2021, 22, 5524. Keywords: axon regeneration; chondroitin sulfate; heparan sulfate; LAR; PTPδ; PTPσ; synapse https://doi.org/10.3390/ijms22115524 Academic Editor: Gonzalo Herradon 1. Introduction Received: 30 April 2021 Type IIa receptor tyrosine phosphatases (RPTPs) have received special attention for Accepted: 20 May 2021 Published: 24 May 2021 three reasons. 1. They serve as presynaptic adhesion molecules that form synapses with specific postsynaptic partners. For example, presynaptic PTPσ, a type IIa RPTP, serves as a Publisher’s Note: MDPI stays neutral synaptic organizer by heterophilic binding to its postsynaptic partners, such as TrkC, Slitrks, with regard to jurisdictional claims in and LRRTM4. 2. They function as receptors for glycans, i.e., heparan sulfate (HS) and published maps and institutional affil- chondroitin sulfate (CS), in the regulation of axon regeneration. Extracellular chondroitin iations. sulfate proteoglycans (CSPGs) overproduced in neural injury serve as glycan ligands to activate the enzymatic activity of PTPσ, and the downstream signaling disrupts autophagy flux and consequently inhibits axon growth. In contrast, heparan sulfate proteoglycans (HSPGs) suppress PTPσ activity and promote axon growth. 3. Combined with 1 and 2, another recent advance in this field is that a glycan, i.e., HS, is now accepted as significant Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. in synapse formation involving type IIa RPTPs. This article is an open access article Focusing on the three points above, this review comprehensively describes the roles distributed under the terms and of type IIa RPTPs and glycans in axon regeneration and synaptogenesis. In addition, conditions of the Creative Commons although axon extension and synapse formation may be orchestrated during development, Attribution (CC BY) license (https:// the underlying regulating mechanisms are still elusive. Extending axons may need to arrest creativecommons.org/licenses/by/ before forming synapses with their target neurons, and such arrest might be regulated by 4.0/). the interactions between type IIa RPTPs and glycans. We also discuss this issue. Int. J. Mol. Sci. 2021, 22, 5524. https://doi.org/10.3390/ijms22115524 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 14 might be regulated by the interactions between type IIa RPTPs and glycans. We also Int. J. Mol. Sci. 2021, 22, 5524 discuss this issue. 2 of 14 2. Roles of Type IIa RPTPs and Glycans in Axon Regeneration and Synaptogenesis 2.1.2. RolesStructures of Type of Type IIa IIa RPTPs RPTPs and Glycans in Axon Regeneration and Synaptogenesis 2.1.T Structureshe type IIa of TypeRPTP IIa family RPTPs consists of three members, LAR, PTPδ, and PTPσ. Each memberThe contains type IIa RPTPthree familyimmunoglobulin consists of three-like members,(Ig) domains, LAR, 3 PTP–8 δfibronectin, and PTPσ .III Each (FNIII) mem- domainsber contains in the three extrace immunoglobulin-likellular region, a single (Ig) transmembrane domains, 3–8 fibronectindomain, and III the (FNIII) intracellu domainslar regionin the composed extracellular of region,a catalytic a single domain transmembrane D1 and non domain,-catalytic and domain the intracellular D2 (Figure region 1). Substratescomposed for of the a catalytic type IIa domain RPTPs D1have and not non-catalytic been fully iden domaintified D2 yet. (Figure This issue1). Substrates will also be for discussedthe type IIalater. RPTPs have not been fully identified yet. This issue will also be discussed later. Figure 1. Structure of type IIa RPTPs. Domains and splice sites of type IIa RPTPs are indicated. Binding molecules and their Figure 1. Structure of type IIa RPTPs. Domains and splice sites of type IIa RPTPs are indicated. Binding molecules and theirbinding binding domains domains are alsoare also depicted. depicted. The Ig domains are essential for ligand binding. CS and HS bind to the same site of The Ig domains are essential for ligand binding. CS and HS bind to the same site of the first Ig domain, Ig1 [1]. There are four multiple-splice sites, named MeA-D (Figure1). the first Ig domain, Ig1 [1]. There are four multiple-splice sites, named MeA-D (Figure 1). MeA and MeB are particularly important for binding to most postsynaptic ligands, e.g., MeA and MeB are particularly important for binding to most postsynaptic ligands, e.g., neurotrophin receptor tyrosine kinase C (TrkC) [2], interleukin-1 receptor accessory protein- neurotrophin receptor tyrosine kinase C (TrkC) [2], interleukin-1 receptor accessory like 1 (IL1RAPL1) [3,4], interleukin-1 receptor accessory protein (IL1RAcp) [5], Slit- and protein-like 1 (IL1RAPL1) [3,4], interleukin-1 receptor accessory protein (IL1RAcp) [5], Trk-like proteins (Slitrks) [6], and synaptic adhesion-like molecule 3 (SALM3) [7], as the Slit- and Trk-like proteins (Slitrks) [6], and synaptic adhesion-like molecule 3 (SALM3) [7], presence or absence of inserts at these sites influences the binding affinity. Although the as the presence or absence of inserts at these sites influences the binding affinity. Although presynaptic HSPG glypicans (GPCs) also bind to type IIa RPTPs, these alternative splicings thedo presynaptic not affect the HSPG bindings glypicans of GPCs (GPCs) and type also IIa bind RPTPs to t [ype8]. This IIa RPTPs is probably, these because alternative HS in splicingthe GPCs do moiety not affect is essential the binding for thes binding,of GPCs andand it type binds IIa to RPTPs the Ig1 [8 domain]. This is as probably described becauseabove (FigureHS in the1). GPC This moiety may also is essential be the case for for the the binding cis-binding, and it betweenbinds to the presynapticIg1 domain asHSPG described neurexin above and (Figure the presynaptic 1). This may PTP σalso. In contrastbe the case to the for above the cis cases,-binding the FNIII between domains the presynapticof type IIa HSPG RPTPs neurexin are critical and for the the presynaptic binding to PTP anotherσ. In contrast important to the postsynaptic above cases, ligand, the FNIIInetrin-G domains ligand of 3 type (NGL3) IIa [RPTPs9,10]. Theare biologicalcritical for significance the binding of to these another bindings important will be postsynapticdiscussed later. ligand, netrin-G ligand 3 (NGL3) [9,10]. The biological significance of these bindingsIt has will been be discussed proposed later. that cis-dimerization of the oligomerization of RPTP negatively regulatesIt has been phosphatase proposed activity that cis through-dimerization the interactionof the oligomerization between intracellular of RPTP negatively domains regulates(this is the phosphatase so-called wedgeactivity model) through (Figure the interaction1)[ 11–13 between], although intracellular the relative domains orientation (this is of theD1 so and-called D2 wedge domains model) upon (Figure ligand-induced 1) [11–13], clusteringalthough the remains relative to orientation be further of verified D1 and [D213 ]. domainsType IIa upon RPTPs ligand have-induced a wedge-shaped clustering remain helix-loop-helixs to be further located verified between [13]. Type the membrane-IIa RPTPs hproximalave a wedge region-shaped and thehelix D1-loop catalytic-helix located domain between (Figure1 the)[ 11 membrane]. The LAR-proximal wedge TATregion peptide and thesuccessfully D1 catalytic inhibits domain LAR