PMID- 10639137
OWN - NLM
STAT- MEDLINE
DCOM- 20000302
LR  - 20191210
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 97
IP  - 2
DP  - 2000 Jan 18
TI  - The putative tumor suppressors EXT1 and EXT2 form a stable complex that
      accumulates in the Golgi apparatus and catalyzes the synthesis of heparan
      sulfate.
PG  - 668-73
AB  - Hereditary multiple exostoses, a dominantly inherited genetic disorder
      characterized by multiple cartilaginous tumors, is caused by mutations in members
      of the EXT gene family, EXT1 or EXT2. The proteins encoded by these genes, EXT1
      and EXT2, are endoplasmic reticulum-localized type II transmembrane glycoproteins
      that possess or are tightly associated with glycosyltransferase 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 activity 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 EXT1 or EXT2 alone, which suggests that the
      complex represents the biologically relevant form of the enzyme(s). These
      findings provide a rationale to explain how inherited mutations in either of the 
      two EXT genes can cause loss of activity, resulting in hereditary multiple
      exostoses.
FAU - McCormick, C
AU  - McCormick C
AD  - Department of Microbiology and Immunology, University of British Columbia,
      Vancouver, BC V6T 1Z3, Canada.
FAU - Duncan, G
AU  - Duncan G
FAU - Goutsos, K T
AU  - Goutsos KT
FAU - Tufaro, F
AU  - Tufaro F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Luminescent Proteins)
RN  - 0 (Macromolecular Substances)
RN  - 0 (Proteins)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 9050-30-0 (Heparitin Sulfate)
RN  - EC 2.4.- (Glycosyltransferases)
RN  - EC 2.4.1.- (N-Acetylglucosaminyltransferases)
RN  - EC 2.4.1.224 (exostosin-1)
RN  - EC 2.4.1.224 (exostosin-2)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Base Sequence
MH  - Catalysis
MH  - Cattle
MH  - Cell Line
MH  - Exostoses, Multiple Hereditary/genetics
MH  - Genes, Tumor Suppressor/genetics
MH  - Glycosyltransferases/metabolism
MH  - Golgi Apparatus/*metabolism
MH  - Green Fluorescent Proteins
MH  - HeLa Cells
MH  - Heparitin Sulfate/*biosynthesis
MH  - Humans
MH  - L Cells
MH  - Luminescent Proteins/genetics
MH  - Macromolecular Substances
MH  - Mice
MH  - Microscopy, Fluorescence
MH  - Molecular Sequence Data
MH  - Mutation
MH  - *N-Acetylglucosaminyltransferases
MH  - Proteins/chemistry/genetics/*metabolism
MH  - Recombinant Fusion Proteins/genetics/metabolism
PMC - PMC15388
EDAT- 2000/01/19 09:00
MHDA- 2000/03/04 09:00
CRDT- 2000/01/19 09:00
PHST- 2000/01/19 09:00 [pubmed]
PHST- 2000/03/04 09:00 [medline]
PHST- 2000/01/19 09:00 [entrez]
AID - 10.1073/pnas.97.2.668 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):668-73. doi: 10.1073/pnas.97.2.668.