Flexible Roles for Proteoglycan Sulfation and Receptor Signaling

Abstract

Proteoglycans (PGs) in the extracellular matrix (ECM) play vital roles in axon growth and navigation, plasticity, and regeneration of injured neurons. Different classes of PGs may support or inhibit cell growth, and their functions are determined in part by highly specific structural features. Among these, the pattern of sulfation on the PG sugar chains is a paramount determinant of a diverse and flexible set of outcomes. Recent studies of PG sulfation illustrate the challenges of attributing biological actions to specific sulfation patterns, and suggest ways in which highly similar molecules may exert opposing effects on neurons. The receptors for PGs, which have yet to be fully characterized, display a similarly nuanced spectrum of effects. Different classes of PG function via overlapping families of receptors and signaling pathways. This enables them to control axon growth and guidance with remarkable specificity, but it poses challenges for determining the precise binding interactions and downstream effects of different PGs and their assorted sulfated epitopes. This review examines existing and emerging evidence for the roles of PG sulfation and receptor interactions in determining how these complex molecules influence neuronal development, growth, and function.

Identification of novel binding sites for heparin in receptor protein-tyrosine phosphatase (RPTPσ): Implications for proteoglycan signaling

“…It is striking that CS-A and CS-C, the major components of CS GAGs in vivo, did not support the binding, consistent with our previous finding for RPTP (6,18). These data emphasize the importance of appreciating the sulfation pattern and sources of CS in interpreting biological data (19). CS-E is not a major component of CS GAGs derived from natural sources.…”

Glycans and glycosaminoglycans in neurobiology: key regulators of neuronal cell function and fate

“…ECM proteoglycans (PGs) play important directive roles in the growth of axons and in the navigation, plasticity and regenerative properties of neurons. PGs have paradoxical roles in neuronal growth and repair processes where they can both promote neuronal growth but in other settings can inhibit neural repair [86]. The sulphation positions and charge density of the GAG side chains of PGs can be sources of important signals to the neurons which either inhibit or promote neuronal repair [86].…”

“…PGs have paradoxical roles in neuronal growth and repair processes where they can both promote neuronal growth but in other settings can inhibit neural repair [86]. The sulphation positions and charge density of the GAG side chains of PGs can be sources of important signals to the neurons which either inhibit or promote neuronal repair [86]. Thus the CS-A and CS-C chains of lectican PGs such as aggrecan, versican, neurocan and brevican are sources of inhibitory signals and a barrier to neural outgrowth in perineural net formations (Fig 3) which surround areas of axonal damage in glial scar formations [87][88][89][90].…”

Proteoglycans in normal physiology and carcinogenesis

“…Степень сульфатирования молекулы ГАГ может варьировать в широких пределах (0-4 SO 4 2-групп/диса-харид) и определяет способность ГАГ/ПГ взаимодей-ствовать с широким кругом различных биологически активных лигандов (в отличие от нейтральных молекул гликопротеинов) [2].…”