Abstract
Receptor protein-tyrosine phosphatase RPTPσ has important functions in modulating neural development and regeneration. Compelling evidence suggests that both heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs) bind to a series of Lys residues located in the first Ig domain of RPTPσ. However, HS promotes and CS inhibits axonal growth. Mutation of these Lys residues abolished binding and signal transduction of RPTPσ to CS, whereas HS binding was reduced, and signaling persisted. This activity was mediated through novel heparin-binding sites identified in the juxtamembrane region. Although different functional outcomes of HS and CS have been previously attributed to the differential oligomeric state of RPTPσ upon GAG binding, we found that RPTPσ was clustered by both heparin and CS GAG rich in 4,6-O-disulfated disaccharide units. We propose an additional mechanism by which RPTPσ distinguishes between HS and CS through these novel binding sites.
Highlights
From the Laboratory of Developmental Neurobiology, Cell Biology and Physiology Center, NHLBI, National Institutes of Health, Bethesda, Maryland 20892
Compelling evidence suggests that both heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs) bind to a series of Lys residues located in the first Ig domain of
We investigated whether complex formation between fulllength RPTP and GAGs impacts the receptor’s enzymatic activity under physiological conditions
Summary
We investigated whether complex formation between fulllength RPTP and GAGs impacts the receptor’s enzymatic activity under physiological conditions. Because HS promotes neuronal outgrowth, we first examined whether the binding of heparin, a close structural relative of HS, to RPTP altered intracellular phosphorylation. To increase baseline Tyr phosphorylation in cells, chick v-Src was cotransfected into 293 cells together with RPTP and its variants. When 293 cells expressing WT RPTP were treated with heparin, the level of Tyr phosphorylation was transiently up-regulated in a dose-dependent manner (Fig. 1, A–C). This up-regulation was abolished by a phosphatase-inactivating mutation of RPTP (D1110E) in the.
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