PMID- 10611230
OWN - NLM
STAT- MEDLINE
DCOM- 20000127
LR  - 20220321
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 20
IP  - 2
DP  - 2000 Jan
TI  - The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples
      ligand-mediated receptor activation from down-regulation.
PG  - 516-22
AB  - A point mutation, Gly380Arg, in the transmembrane domain of fibroblast growth
      factor receptor 3 (FGFR3) leads to achondroplasia, the most common form of
      genetic dwarfism in humans. This substitution was suggested to enhance mutant
      receptor dimerization, leading to constitutive, ligand-independent activation. We
      found that dimerization and activation of the G380R mutant receptor are
      predominantly ligand dependent. However, using both transient and stable
      transfections, we found significant overexpression only of the mutant receptor
      protein. Metabolic pulse-chase experiments, cell surface labeling, and kinetics
      of uptake of radiolabeled ligand demonstrated a selective delay in the
      down-regulation of the mutant receptor. Moreover, this receptor was now resistant
      to ligand-mediated internalization, even at saturating ligand concentrations.
      Finally, transgenic mice expressing the human G380R mutant receptor under the
      mouse receptor transcriptional control demonstrated a markedly expanded area of
      FGFR3 immunoreactivity within their epiphyseal growth plates, compatible with an 
      in vivo defect in receptor down-regulation. We propose that the achondroplasia
      mutation G380R uncouples ligand-mediated receptor activation from down-regulation
      at a site where the levels and kinetics of FGFR3 signals are crucial for
      chondrocyte maturation and bone formation.
FAU - Monsonego-Ornan, E
AU  - Monsonego-Ornan E
AD  - Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 
      76100, Israel.
FAU - Adar, R
AU  - Adar R
FAU - Feferman, T
AU  - Feferman T
FAU - Segev, O
AU  - Segev O
FAU - Yayon, A
AU  - Yayon A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Ligands)
RN  - 0 (Proto-Oncogene Proteins c-fos)
RN  - 0 (Receptors, Fibroblast Growth Factor)
RN  - EC 2.7.10.1 (FGFR3 protein, human)
RN  - EC 2.7.10.1 (Fgfr3 protein, mouse)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 3)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Amino Acid Substitution/*genetics
MH  - Animals
MH  - Bone Development
MH  - Cell Line
MH  - Cell Membrane/metabolism
MH  - Chondrocytes/cytology/metabolism
MH  - Dimerization
MH  - *Down-Regulation
MH  - Endocytosis
MH  - Growth Plate/metabolism
MH  - Humans
MH  - Kinetics
MH  - Ligands
MH  - Mice
MH  - Mice, Transgenic
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Molecular Weight
MH  - Phosphorylation
MH  - Protein Processing, Post-Translational
MH  - *Protein-Tyrosine Kinases
MH  - Proto-Oncogene Proteins c-fos/metabolism
MH  - Receptor Aggregation
MH  - Receptor, Fibroblast Growth Factor, Type 3
MH  - Receptors, Fibroblast Growth Factor/chemistry/*genetics/*metabolism
MH  - Signal Transduction
PMC - PMC85119
EDAT- 1999/12/28 00:00
MHDA- 1999/12/28 00:01
CRDT- 1999/12/28 00:00
PHST- 1999/12/28 00:00 [pubmed]
PHST- 1999/12/28 00:01 [medline]
PHST- 1999/12/28 00:00 [entrez]
AID - 10.1128/MCB.20.2.516-522.2000 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2000 Jan;20(2):516-22. doi: 10.1128/MCB.20.2.516-522.2000.