Role of Chondroitin Sulfate (CS) Modification in the Regulation of Protein-tyrosine Phosphatase Receptor Type Z (PTPRZ) Activity

Abstract

Protein-tyrosine phosphatase receptor type Z (PTPRZ) is predominantly expressed in the developing brain as a CS proteoglycan. PTPRZ has long (PTPRZ-A) and short type (PTPRZ-B) receptor forms by alternative splicing. The extracellular CS moiety of PTPRZ is required for high-affinity binding to inhibitory ligands, such as pleiotrophin (PTN), midkine, and interleukin-34; however, its functional significance in regulating PTPRZ activity remains obscure. We herein found that protein expression of CS-modified PTPRZ-A began earlier, peaking at approximately postnatal days 5-10 (P5-P10), and then that of PTN peaked at P10 at the developmental stage corresponding to myelination onset in the mouse brain. Ptn-deficient mice consistently showed a later onset of the expression of myelin basic protein, a major component of the myelin sheath, than wild-type mice. Upon ligand application, PTPRZ-A/B in cultured oligodendrocyte precursor cells exhibited punctate localization on the cell surface instead of diffuse distribution, causing the inactivation of PTPRZ and oligodendrocyte differentiation. The same effect was observed with the removal of CS chains with chondroitinase ABC but not polyclonal antibodies against the extracellular domain of PTPRZ. These results indicate that the negatively charged CS moiety prevents PTPRZ from spontaneously clustering and that the positively charged ligand PTN induces PTPRZ clustering, potentially by neutralizing electrostatic repulsion between CS chains. Taken altogether, these data indicate that PTN-PTPRZ-A signaling controls the timing of oligodendrocyte precursor cell differentiation in vivo, in which the CS moiety of PTPRZ receptors maintains them in a monomeric active state until its ligand binding.Myelination is an essential feature of the vertebrate nervous system that electrically insulates axons, thereby enabling the salutatory transmission of nerve impulses. Oligodendrocyte precursor cells (OPCs) 2 are the principal source of myelinating oligodendrocytes (1). Previous studies reported that protein tyrosine phosphorylation is crucially involved in the signal transduction mechanism for OPC differentiation into mature oligodendrocytes and myelin formation. FYN kinase in the Src tyrosine kinase family is the most prominent member involved in OPC differentiation and myelin formation (2). FYN activity is up-regulated during oligodendrocyte differentiation (3, 4), and Fyn-knock-out mice exhibit hypomyelination in the brain (5, 6). FYN phosphorylates p190 RhoGAP, a GTPase-activating protein (GAP) for Rho GTPase, to suppress Rho/ROCK, resulting in the maturation of oligodendrocytes and myelination (7,8).PTPRZ is the most abundant receptor-type protein-tyrosine phosphatase (RPTP) in OPCs (9, 10). PTPRZ dephosphorylates p190 RhoGAP, thereby acting as a counterpart of FYN (11,12). The amounts of myelin basic protein (MBP) and myelinated axons in the brain at postnatal day 10, when myelination occurs, are significantly higher in Ptprz-deficient mice than in wildtype animals, indicating a suppre...

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance ofKS‐glycodynamics and interactive capability with neuroregulatory ligands

“…Signaling of pleiotrophin through RPTP‐ζ is involved in the activation of oligodendrocyte progenitor cells (Kuboyama et al . ) and oligodendrocyte differentiation (Asai et al . ) and regulates the morphogenesis of Purkinje cell dendrites in the developing cerebellum and hippocampus (Asai et al .…”

“…PTN is a phosphacan ligand and its binding is influenced by the sulfation pattern of the GAG side chains of phosphacan (Maeda et al 2003). Signaling of pleiotrophin through RPTP-f is involved in the activation of oligodendrocyte progenitor cells (Kuboyama et al 2016) and oligodendrocyte differentiation (Asai et al 2009) and regulates the morphogenesis of Purkinje cell dendrites in the developing cerebellum and hippocampus (Asai et al 2009). Contactin-1 binds CS-E and this promotes axonal outgrowth (Mikami et al 2009;Nakanishi et al 2012).…”

The PTN‐PTPRZ signal activates the AFAP1L2‐dependent PI3K‐AKT pathway for oligodendrocyte differentiation: Targeted inactivation of PTPRZ activity in mice

“…In contrast, protein tyrosine phosphatase receptor type Z (PTPRZ, also called PTPζ), one of the most abundant PTPs in OPCs (Ranjan & Hudson, ; Sim et al, ), functions to maintain OPCs in an undifferentiated state (Fujikawa & Noda, ; Kuboyama et al, ; Kuboyama, Fujikawa, Suzuki, & Noda, ; Kuboyama, Fujikawa, Suzuki, Tanga, & Noda, ; Kuboyama, Tanga, Suzuki, Fujikawa, & Noda, ). Two transmembrane isoforms, PTPRZ‐A and PTPRZ‐B, and one secretory isoform, PTPRZ‐S (also known as phosphacan or 6B4 proteoglycan) corresponding to the extracellular portion of PTPRZ‐A, are generated from a single PTPRZ gene by alternative splicing (Chow, Fujikawa, Shimizu, Suzuki, & Noda, ; Krueger & Saito, ; Levy et al, ; Maeda, Hamanaka, Shintani, Nishiwaki, & Noda, ).…”

“…The three isoforms expressed in the CNS belong to chondroitin sulfate proteoglycans (CSPGs) because they are highly glycosylated by chondroitin sulfate chains (Chow, Fujikawa, Shimizu, & Noda, ; Nishiwaki, Maeda, & Noda, ). The chondroitin sulfate moiety is required for the high‐affinity binding of endogenous ligands, such as pleiotrophin (PTN), midkine, and interleukin‐34 (Kuboyama et al, ; Maeda et al, ; Maeda, Nishiwaki, Shintani, Hamanaka, & Noda, ; Nandi et al, ). These three ligands enhance OPC differentiation in primary glial cell cultures in vitro (Kuboyama et al, ) by inactivating the intracellular PTPase activity of PTPRZ (Fukada, Kawachi, Fujikawa, & Noda, ; Kuboyama et al, ; Maeda et al, ).…”

Structural basis for ligand-induced inactivation of protein tyrosine receptor type Z (PTPRZ): Physiological relevance of head-to-toe RPTP dimerization

“…We transfected four constructs (11,17). The three mutants showed patchy distributions upon the PTN treatment as well as wild-type PTPRZ-B (compare "con" to "PTN" in Fig.…”