and KAKENHI 20K07735 to T.O. Institutional Review Table Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. Footnotes Publishers Notice: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.. and its HS is essential for the binding between these three molecules. Another Thymol HSPG, glypican 4, binds to presynaptic PTP and postsynaptic LRRTM4 in an HS-dependent manner. Type IIa RPTPs are also involved in the formation of excitatory and inhibitory synapses by heterophilic binding to a variety of postsynaptic partners. We also discuss the important issue of possible mechanisms coordinating axon extension and synapse formation. strong class=”kwd-title” Keywords: axon regeneration, chondroitin sulfate, heparan sulfate, LAR, PTP, PTP, synapse 1. Introduction Type IIa receptor tyrosine phosphatases (RPTPs) have received special attention for three reasons. 1. They serve as presynaptic adhesion molecules that form synapses with specific postsynaptic partners. For example, presynaptic PTP, a type IIa RPTP, serves as a synaptic organizer by heterophilic binding to its postsynaptic partners, such as TrkC, Slitrks, and LRRTM4. 2. They function as receptors for glycans, i.e., heparan sulfate (HS) and chondroitin sulfate (CS), in the regulation of axon regeneration. Extracellular chondroitin sulfate proteoglycans (CSPGs) overproduced in neural injury serve as glycan ligands to activate the enzymatic activity of PTP, and the downstream signaling disrupts autophagy flux and consequently inhibits axon growth. In contrast, heparan sulfate proteoglycans (HSPGs) suppress PTP activity and promote axon growth. 3. Combined with 1 and 2, another recent advance in this field is usually that a glycan, i.e., HS, is now accepted as significant in synapse formation including type IIa RPTPs. Focusing on the three points above, this review comprehensively explains the functions of type IIa RPTPs and glycans in axon regeneration and synaptogenesis. In addition, although axon extension and synapse formation may be orchestrated during development, the underlying regulating mechanisms are still elusive. Extending axons may need to arrest before forming synapses with their target neurons, and such arrest might be regulated by the interactions between type IIa RPTPs and glycans. We also discuss this issue. 2. Functions of Type IIa RPTPs and Glycans in Axon Regeneration and Synaptogenesis 2.1. Structures of Thymol Type IIa RPTPs The type IIa RPTP family consists of Thymol three users, LAR, PTP, and PTP. Each member contains three immunoglobulin-like (Ig) domains, 3C8 fibronectin III (FNIII) domains in the extracellular region, a single transmembrane domain name, and the intracellular region composed of a catalytic domain name D1 and non-catalytic domain name D2 (Physique 1). Substrates for the type IIa RPTPs have not been fully recognized yet. This issue will also be discussed later. Open in a separate window Physique 1 Structure of type IIa RPTPs. Domains and splice sites of type IIa RPTPs are indicated. Binding molecules and their binding domains are also depicted. The Ig domains are essential for ligand binding. CS and HS bind to the same site of the first Ig domain name, Ig1 . You will find four multiple-splice sites, named MeA-D (Physique 1). MeA and MeB are particularly important for binding to most postsynaptic ligands, e.g., neurotrophin receptor tyrosine kinase C (TrkC) , interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) [3,4], interleukin-1 receptor accessory protein (IL1RAcp) , Slit- and Trk-like proteins (Slitrks) , and synaptic adhesion-like molecule 3 (SALM3) , as the presence or absence of inserts at these sites influences the binding affinity. Even though presynaptic HSPG glypicans (GPCs) also bind to type IIa RPTPs, these option splicings do not impact the bindings of GPCs Thymol and type IIa RPTPs . This is probably because HS in the GPC moiety is essential for the binding, and it binds to the Ig1 domain name as explained above (Physique 1). This may also be the case for the cis-binding between the presynaptic HSPG neurexin and the presynaptic PTP. In contrast to the above cases, the FNIII domains of type IIa RPTPs are critical for Rabbit polyclonal to ALS2CL the binding to another important postsynaptic ligand, netrin-G ligand 3 (NGL3) [9,10]. The biological significance of these bindings will be discussed later. It has been proposed that cis-dimerization of the oligomerization of RPTP negatively regulates phosphatase activity through the conversation between intracellular domains (this is the so-called wedge model) (Physique 1) [11,12,13], even though relative orientation of D1 and D2 domains upon ligand-induced clustering remains to be further verified . Type IIa RPTPs have a wedge-shaped helix-loop-helix located between the membrane-proximal region and the D1 catalytic domain name (Physique 1) . The LAR wedge TAT peptide successfully inhibits LAR function . Intracellular sigma peptide (ISP), a peptide-mimetic of the PTP wedge with a TAT domain name, can also suppress PTP activity . 2.2. Axon Regeneration 2.2.1. Type IIa RPTPs and Glycosaminoglycans in Axon RegenerationNeural injuries damage axons. The portion distal to the injury site undergoes so-called Wallerian degeneration and thus disappears.