Fam20B Gain-of-Function Blocks The synthesis of Glycosaminoglycan Chains of Proteoglycans and inhibits proliferation and migration of glioblastoma cells

Heparan-sulfate (HS) and chondroitin-sulfate (CS) proteoglycans (PGs) are essential regulators of many biological processes including cell differentiation, signalisation and proliferation. PGs interact, mainly via their glycosaminoglycan (GAG) chains, with a large number of ligands including growth factors, enzymes and extracellular matrix components, thereby modulating their biological activities. HSPGs and CSPGs share a common tetrasaccharide linker region, which undergoes modifications particularly phosphorylation of the xylose residue by the kinase Fam20B. Here, we demonstrated that Fam20B gain-of-function decreased, in a dose dependent manner, the synthesis of both CS- and HS-attached PGs. In addition, we showed that blockage of GAG chain synthesis by Fam20B was suppressed by mutation of aspartic acid residues D289 and D309 of the catalytic domain. Interestingly, we bring evidence that, in contrast to Fam20B, expression of the 2-phosphoxylose phosphatase XYLP increased, in a dose dependent manner, GAG chain synthesis and rescue the blockage of GAG chains synthesis induced by Fam20B. In line with previous reports, we found that Fam20B loss-of-function reduced GAG chain synthesis. Finaly, we found that Fam20B inhibits proliferation and migration of glioblastoma cells, thus revealing the critical role of GAG chains of PGs in glioblastoma cell tumorigenesis. This study revealed that both gain- and loss-of-function of Fam20B led to decreased GAG chain synthesis, therefore suggesting that a balance between phosphorylation and dephosphorylation of the xylose by Fam20B and XYLP, respectively is probably an essential factor of the regulation of the rate of PG synthesis.