THE PUTATIVE TUMOR SUPPRESSORS EXT1 AND EXT2 ARE GLYCOSYLTRANSFERASESREQUIRED FOR THE BIOSYNTHESIS OF HEPARAN-SULFATE

Hereditary multiple exostoses, characterized by multiple cartilaginous tumors, is ascribed to mutations at three distinct loci, denoted EXT1 -3. Here, we report the purification of a protein from bovine serum th at harbored the D-glucuronyl (GlcA) and N-acetyl-D-glucosaminyl (GlcNA c) transferase activities required for biosynthesis of the glycosamino glycan, heparan sulfate (HS). This protein was identified as EXT2. Exp ression of EXT2 yielded a protein with both glycosyltransferase activi ties. Moreover, EXT1, previously found to rescue defective HS biosynth esis (McCormick, C., Leduc, Y., Martindale, D., Mattison, K., Esford, L. E., Dyer, A. P., and Tufaro, F. (1998) Nat. Genet. 19, 158-161), wa s shown to elevate the low GlcA and GlcNAc transferase levels of mutan t cells. Thus at least two members of the EXT family of tumor suppress ors encode glycosyltransferases involved in the chain elongation step of HS biosynthesis.