The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate

Hereditary multiple exostoses, a dominantly inherited genetic disorder char acterized by multiple cartilaginous tumors, is caused by mutations in membe rs of the EXT gene family, EXT? or EXT2, The proteins encoded by these gene s, EXT1 and EXT2, are endoplasmic reticulum-localized type II transmembrane glycoproteins that possess or are tightly associated with glycosyltransfer ase activities involved in the polymerization of heparan sulfate, Here, by testing a cell line with a specific defect in EXT1 in in vivo and in vitro assays, we show that EXT2 does not harbor significant glycosyltransferase a ctivity in the absence of EXT1, Instead, it appears that EXT1 and EXT2 form a hetero-oligomeric complex in vivo that leads to the accumulation of both proteins in the Golgi apparatus. Remarkably, the Golgi-localized EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than E XT1 or EXT2 alone, which suggests that the complex represents the biologica lly relevant form of the enzyme(s), These findings provide a rationale to e xplain how inherited mutations in either of the two EXT genes can cause los s of activity, resulting in hereditary multiple exostoses.