EXTL3 is a bifunctional glycosyltransferase with dual roles in cellular biology. As a glycosyltransferase, EXTL3 catalyzes heparan sulfate (HS) biosynthesis in the Golgi apparatus, functioning as both a chain initiator and elongator through alpha-1,4-N-acetylglucosaminyl transferase activity 1. The enzyme contains a multi-domain architecture with two glycosyltransferase domains and a coiled-coil domain, with critical N-glycosylation sites required for proper folding 2. Beyond glycosyltransferase function, EXTL3 acts as a receptor for regenerating islet-derived (REG) proteins, activating downstream signaling pathways including PI3K-AKT and RAS-RAF-MEK-ERK cascades. This REG-receptor function is essential for REG3A-mediated keratinocyte proliferation, skin inflammation inhibition via PI3K-AKT-STAT3 signaling, and glucose tolerance regulation in pancreatic tissue 3. EXTL3 also participates in baculovirus transduction through HS biosynthesis-dependent viral attachment and entry mechanisms 4. Clinically, biallelic EXTL3 mutations cause immunoskeletal dysplasia with neurodevelopmental abnormalities 3. Dysregulation occurs in mucinous colorectal cancer through promoter methylation-mediated silencing 5, and reduced EXTL3 expression correlates with worse prognosis in prostate cancer and altered immune checkpoint function 6. Gene silencing approaches show therapeutic potential for heparan sulfate-storing mucopolysaccharidoses 7.