Structural deciphering of the NG2/CSPG4 proteoglycan multifunctionality

Abstract

The chondroitin sulfate proteoglycan 4 (CSPG4) gene encodes a transmembrane proteoglycan (PG) constituting the largest and most structurally complex macromolecule of the human surf aceome. Its transcript shows an extensive evolutionary conservation and, due to the elaborated intracellular processing of the translated protein, it generates an array of glycoforms with the potential to exert variant‐specific functions. CSPG4‐mediated molecular events are articulated through the interaction with more than 40 putative ligands and the concurrent involvement of the ectodomain and cytoplasmic tail. Alternating inside‐out and outside‐in signal transductions may thereby be elicited through a tight functional connection of the PG with the cytoskeleton and its regulators. The potential of CSPG4 to influence both types of signaling mechanisms is also asserted by its lateral mobility along the plasma membrane and its intersection with microdomain‐restricted internalization and endocytic trafficking. Owing to the multitude of molecular interplays that CSPG4 may engage, and thanks to a differential phosphorylation of its intracellular domain accounted by crosstalking signaling pathways, the PG stands out for its unique capability to affect numerous cellular phenomena, including those purporting pathologic conditions. We discuss here the progresses made in advancing our understanding about the structural‐functional bases for the ability of CSPG4 to widely impact on cell behavior, such as to highlight how its multivalency may be exploited to interfere with disease progression.—Tamburini, E., Dallatomasina, A., Quartararo, J., Cortelazzi, B., Mangieri, D., Lazzaretti, M., Perris, R. Structural deciphering of the NG2/CSPG4 proteoglycan multifunctionality. FASEB J. 33, 3112–3128 (2019). http://www.fasebj.org

iPS-Derived Early Oligodendrocyte Progenitor Cells from SPMS Patients Reveal Deficient In Vitro Cell Migration Stimulation

“…We showed here that the addition of NG2 recombinant protein to the CM produced by control OPC-like cells causes an inhibitory effect on cell migration but an activating effect when NG2 is combined with SPMS-derived CM, suggesting the fine regulation of NG2 concentration on migration signaling. It is possible that NG2/CSPG4 stimulation of cell migration works in a concentration range and depends on other factors present in the media, as CSPG4-mediated molecular events are articulated through the interaction with more than 40 putative ligands [ 50 ]. Additionally, it has been described that NG2/CSPG4 posttranslational modification domains are crucial for proper signaling and cell function [ 50 ].…”

“…It is possible that NG2/CSPG4 stimulation of cell migration works in a concentration range and depends on other factors present in the media, as CSPG4-mediated molecular events are articulated through the interaction with more than 40 putative ligands [ 50 ]. Additionally, it has been described that NG2/CSPG4 posttranslational modification domains are crucial for proper signaling and cell function [ 50 ]. We cannot discard that the presence of plasma membrane NG2 at normal levels is needed, as it has been described to be a core organizer of Rho GTPase activity and localization in the cell, controlling OPC polarity and directional migration [ 49 ].…”

The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair

“…While CS-A- and CS-C-substituted lectican PGs inhibit neural outgrowth and functional neuronal recovery in gliotic scars following SCI and TBI, some CS-PGs, such as phosphacan [ 170 ], NG2 (CSPG4) [ 171 ] and neuroglycan C (CSPG5) [ 172 ], decorated with CS-E can reverse this inhibitory signalling to promote neuritogenesis and functional recovery of neural tissues.…”

The Role of Chondroitin Sulfate Proteoglycans in Nervous System Development

“…199 Developing oligodendrocytes in the hippocampus transiently express NG2, also known as CSPG4 and melanoma chondroitin sulfate proteoglycan (MCSP), a transmembrane protein with a single GAG attachment site. 200 In culture, NG2 has an inhibitory role on neuronal process outgrowth, due to both the single GAG chain and the core protein. 201,202 While NG2 has been used as a marker of OPCs, a functional role for NG2 in the nervous system has only been revealed in the NG2-knockout mouse.…”