NG2 proteoglycan

Neural/glial antigen 2, or NG2, is a rat integral membrane proteoglycan found in the plasma membrane of many diverse cell types.[1] Homologous proteins in other species include human CSPG4, also known as melanoma-associated chondroitin sulfate proteoglycan (MCSP), Mouse AN2, and Sea urchin ECM3.[2] This single-pass transmembrane molecule may be plasma membrane-bound or secreted and associated with the extracellular matrix.[3] It is believed to play a role in functions such as cell adhesion, cell-cell and cell-ECM communication, migration and metastasis, proliferation, and axonal growth, guidance and regeneration. NG2-positive cells include oligodendrocyte progenitor cells (OPCs) and other progenitor cell populations, such as chondroblasts, myoblasts, and pericytes, as well as several different tumors including glioblastoma multiforme and melanoma.[4][5][6][7][8][9][10]

Structure

NG2 cDNA contains 8,071 nucleotides corresponding to 2,325 amino acids. The entire protein is divided into three domains: a large extracellular domain (2,224 amino acids), a single transmembrane domain (25 amino acids), and a short cytoplasmic tail (76 amino acids). The extracellular domain is further subdivided into three subdomains: an N-terminal globular domain that contains several cysteines and is stabilized by intrachain disulfide bonds; a central domain to which the chondroitin sulfate moiety covalently binds; and a juxtamembrane domain also containing several cysteines. The core NG2 molecule is approximately 300 kDa and the addition of at least one chondroitin sulfate molecule results in a molecule that is 400 – 800 kDa.[1]

Localization

NG2 is found both in the central nervous system (CNS) and peripherally in a variety of tissues. In the CNS, NG2 may be found on pericytes,[4] various tumors including glioblastoma,[5][6][7] and a population of progenitor cells known as polydendrocytes or oligodendrocyte precursor cells (OPCs).[8] Peripherally, NG2 is found on chondroblasts, cardiomyocytes, aortic smooth muscle cells, myoblasts, and several different human tumors, including melanoma.[9][10] Recently, when co-localized with S100β, NG2 has been shown to be a marker of terminal, or perisynaptic, Schwann cells at the neuromuscular junction.[11] Although NG2 is a single-pass transmembrane protein, it may also be released by proteolytic cleavage into the extracellular space where it associates with the extracellular matrix (ECM).[3] The levels of NG2 have been shown to increase rapidly at areas of injury in the CNS, including in the area of the glial scar of spinal cord contusion injury.[2][12][13][14]

Interacting molecules

NG2 interacts via its large extracellular domain with many factors in the extracellular space. Within its central extracellular domain, NG2 has a binding site for Type VI collagen as well as PDGF-AA. At its juxtamembrane domain, NG2 may interact with bFGF.[15]

References
  1. Nishiyama A, Dahlin KJ, Prince JT, Johnstone SR, Stallcup WB. "The primary structure of NG2: a novel membrane-spanning proteoglycan." J Cell Biol. 1991 Jul;114(2):359-71. PMID 1906475.
  2. Asher RA, Morgenstern DA, Fawcett JW. "Chondroitin sulphate proteoglycans: inhibitory components of the glial scar." Prog Brain Res. 2001;132:611-9. PMID 11545024.
  3. Nishiyama A, Lin ZH, Stallcup WB. "Generation of truncated forms of the NG2 proteoglycan by cell surface proteolysis." Mol Biol Cell. 1995 Dec;6(12):1819-32. PMID 8590808
  4. Ozerdem U, Grako KA, Dahlin-Huppe K, Monosov E, Stallcup WB. "NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis." Dev. Dyn. (2001 Oct) 222(2):218 – 227. PMID 11668599
  5. Al-Mayhani MT, Grenfell R, Narita M, Piccirillo S, Kenney-Herbert E, Fawcett JW, Collins VP, Ichimura K, Watts C. "NG2 expression in glioblastoma identifies an actively proliferating population with an aggressive molecular signature." Neuro Oncol. 2001 Aug; 13(8):830-45. PMID 21798846
  6. Girolamo F, Dallatomasina A, Rizzi M, Errede M, Walchli T, Mucignat MT, Frei K, Roncali L, Perris R, and Virgintino D. "Diversified expression of NG2/CSPG4 isoforms in glioblastoma and human foetal brain identifies pericytes subsets." PLoS One. 2013 Dec 26;8(12):e84883. PMID 24386429.
  7. Poli A, Wang J, Domingues O, Planaguma J, Yan T, Rygh CB, Skaftnesmo KO, Thorsen F, McCormack E, Hentges F, Pedersen PH, Zimmer J, Enger PO, Chekenya M. "Targeting glioblastoma with NK cells and mAb against MG2/CSPG4 prolongs animal survival." Oncotarget. 2013 Sep;4(9):1527-46. PMID 24127551
  8. Levine JM, Reynolds R, Fawcett JW. "The oligodendrocyte precursor cell in health and disease." Trends Neurosci. 2001 Jan;24(1):39-47. PMID 11163886.
  9. Stallcup WB. "The NG2 proteoglycan: past insights and future prospects." J. Neurocytol. 2002 Jul-Aug;31(6-7):423-35. PMID 14501214
  10. Levine JM, Nishiyama A. "The NG2 chondroitin sulfate proteoglycan: a multifunctional proteoglycan associated with immature cells." Perspect Dev Neurobiol. 1996;3(4):245-59. PMID 9117258
  11. Castro et al. (2020) Specific labeling of synaptic Schwann cells reveals unique cellular and molecular features. 2020;9:e56935 DOI:10.7554/eLife.56935. PMID 32584256
  12. Jones LL, Yamaguchi Y, Stallcup WB, Tuszynski MH. "NG2 is a major chondroitin sulfate proteoglycan produced after spinal cord injury and is expressed by macrophages and oligodendrocyte progenitors." J Neurosci. 2002 Apr 1;22(7):2792-803. PMID 11923444
  13. Levine JM. "Increased expression of the NG2 chondroitin-sulfate proteoglycan after brain injury." J. Neurosci. 1994 Aug;14(8):4716-30. PMID 8046446
  14. Zhang Y, Tohyama K, Winterbottom JK, Haque NS, Schachner M, Lieberman AR, Anderson PN. "Correlation between putative inhibitory molecules at the dorsal root entry zone and failure of dorsal root axonal regeneration." Mol Cell Neurosci. 2001 Mar;17(3):444-59. PMID 11273641.
  15. Tillet et al. 1997, Goretzki et al. 1999
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