Phosphacan, a chondroitin sulfate proteoglycan of brain that interacts with neurons and neural cell-adhesion molecules, is an extracellular variant of a receptor-type protein tyrosine phosphatase.

Abstract

We We have previously described a chondroitin sulfate proteoglycan isolated from a phosphate-buffered saline extract of rat brain by immunoaffinity chromatography with the 3F8 monoclonal antibody and which is developmentally regulated with respect to its sulfation, carbohydrate composition and oligosaccharide structure, and immunocytochemical localization (1). A chondroitin/keratan sulfate proteoglycan (designated 3H1) was also isolated from rat brain by using monoclonal antibodies to the keratan sulfate chains (1). 3F8 and neurocan, another chondroitin sulfate proteoglycan of brain, for which the primary structure has been described (2), interact with neurons and the neural cell-adhesion molecules (CAMs), Ng-CAM and N-CAM (3). From radioligandbinding studies it was found that the brain proteoglycans bind with high affinity (Kd "O.5 nM) to Ng-CAM and N-CAM but not to other cell-surface and extracellular matrix proteins such as laminin, fibronectin, several collagens, epidermal growth factor and fibroblast growth factor receptors, or the myelin-associated glycoprotein (4). The 3F8 proteoglycan and neurocan inhibited neurite outgrowth and binding of neurons to Ng-CAM when mixtures of these proteins were adsorbed to polystyrene dishes, and direct binding ofneurons to the proteoglycan core glycoproteins was demonstrated with an assay in which cell-substrate contact was initiated by centrifugation (3,4). Recent studies have also shown that embryonic chicken brain neurons bind the 3H1 proteoglycan and contain cell-surface keratan sulfate chains (M. Flad, R.U.M., and R.K.M., unpublished results). These results indicate that brain proteoglycans can bind to neurons and that Ng-CAM and N-CAM may be heterophilic ligands for neurocan and the 3F8 and 3H1 proteoglycans.The primary structure of the 3F8 proteoglycan has now been determined by cDNA cloning, and we have identified this major chondroitin sulfate proteoglycan of brain as a possible mRNA splice variant of a receptor-type protein tyrosine phosphatase (PTP) named PTPC (5) and RPTFP. (6) (RPTPC/P). The tyrosine phosphatases act in concert with tyrosine kinases to regulate the phosphorylation state of proteins, and their structural features and potential physiological roles in signal transduction and cell-cycle regulation have recently been reviewed (7-9). With probes based on conserved sequences in their phosphatase domains, over 30 PTPs have now been cloned, but a major question concerning this family of key regulatory enzymes is the identification of their ligands and substrates. Our fidings indicate that neural CAMs and the exellular matrix protein tenascin may serve as ligands for RPIPC/P. Amino acid sequencing of the 3H1 chondroitin/keratan sulfate proteoglycan of brain demonstrated that it is a glycosylation variant of the 3F8 proteoglycan. We have named the 3F8/3H1 proteoglycan phosphacant and suggest that it may modulate cell interactions and other developmental processes in nervous tissue.

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

“…43 There are four splicing isoforms of PTPRZ1, two of which are transmembrane receptor forms (RPTPb, short and long) and the other two are soluble forms that lack both a transmembrane region and tyrosine phosphatase activity (phosphacan, short and long). [44][45][46][47][48][49][50] The extracellular region of PTPRZ1 consists of several modular structural domains, including a carbonic anhydrase domain, a fibronectin type III repeat, a spacer domain (all of which are present in all four isoforms), and a region containing B860 amino acids (that is missing in the RPTPb and phosphacan short forms) where several glycosaminoglycan chains can be attached. 44 The carbonic anhydrase domain interacts with the cell recognition molecule contactin, 51 whereas the spacer region can interact with several other cell adhesion molecules including NrCAM, L1CAM, NCAM, contactin-1 and contactin-2/TAG-1.…”

The Fibrinogen-like Globe of Tenascin-C Mediates Its Interactions with Neurocan and Phosphacan/Protein-tyrosine Phosphatase-ζ/β

“…The three potential chondroitin sulfate attachment sites that are most likely to be utilized are all located in the C-terminal portion of the phosphacan core protein, although additional attachment sites may be present more N-terminally at Ser-595 and Ser-645 (3,4). In electron micrographs one sees fine thread-like structures (Fig.…”

“…It contains N-terminal immunoglobulin-like and hyaluronanbinding domains, a C-terminal domain consisting of EGF-, lectin-, and complement regulatory protein-like sequences, and a nonhomologous central domain of 593 amino acids, which contains the attachment sites for the three chondroitin sulfate chains and a large number of O-glycosidic oligosaccharides. In contrast, phosphacan (4,5), which contains a 173-kDa core protein and three chondroitin sulfate chains, is an mRNA splicing product that represents the entire extracellular domain of a receptor-type protein-tyrosine phosphatase that also occurs as a chondroitin sulfate proteoglycan in brain (3). Phosphacan and protein-tyrosine phosphatase /␤ have an N-terminal carbonic anhydrase-like domain followed by a fibronectin type III sequence.…”

Versican V2 Assembles the Extracellular Matrix Surrounding the Nodes of Ranvier in the CNS

“…The trimeric TnR and the hexameric TnC glycoproteins may cross-link the G3 domains of lecticans and, thus, tie up the extracellular network (Lundell et al, 2004). Finally, phosphacan, a secreted CSPG form of the receptor-like protein tyrosine phosphatase ␤ (RPTP␤) (Maurel et al, 1994), joins the complex.…”