The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation

被引:115
作者
Monsonego-Ornan, E
Adar, R
Feferman, T
Segev, O
Yayon, A [1 ]
机构
[1] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel
[2] ProChon Biotech Ltd, Kiryat Weizmann, IL-76100 Rehovot, Israel
关键词
D O I
10.1128/MCB.20.2.516-522.2000
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:516 / 522
页数:7
相关论文
共 42 条
[1]   THE FGF FAMILY OF GROWTH-FACTORS AND ONCOGENES [J].
BASILICO, C ;
MOSCATELLI, D .
ADVANCES IN CANCER RESEARCH, 1992, 59 :115-165
[2]   Hypochondroplasia: Molecular analysis of the fibroblast growth factor receptor 3 gene [J].
Bellus, GA ;
McIntosh, I ;
Szabo, J ;
Aylsworth, A ;
Kaitila, I ;
Francomano, CA .
MOLECULAR AND DEVELOPMENTAL BIOLOGY OF CARTILAGE, 1996, 785 :182-187
[3]   CHONDROCYTE DIFFERENTIATION [J].
CANCEDDA, R ;
CANCEDDA, FD ;
CASTAGNOLA, P .
INTERNATIONAL REVIEW OF CYTOLOGY - A SURVEY OF CELL BIOLOGY, VOL 159, 1995, 159 :265-358
[4]   ABNORMAL BONE-GROWTH AND SELECTIVE TRANSLATIONAL REGULATION IN BASIC FIBROBLAST GROWTH-FACTOR (FGF-2) TRANSGENIC MICE [J].
COFFIN, JD ;
FLORKIEWICZ, RZ ;
NEUMANN, J ;
MORTHOPKINS, T ;
DORN, GW ;
LIGHTFOOT, P ;
GERMAN, R ;
HOWLES, PN ;
KIER, A ;
OTOOLE, BA ;
SASSE, J ;
GONZALEZ, AM ;
BAIRD, A ;
DOETSCHMAN, T .
MOLECULAR BIOLOGY OF THE CELL, 1995, 6 (12) :1861-1873
[5]   Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3 [J].
Colvin, JS ;
Bohne, BA ;
Harding, GW ;
McEwen, DG ;
Ornitz, DM .
NATURE GENETICS, 1996, 12 (04) :390-397
[6]   Abnormal FGFR 3 expression in cartilage of thanatophoric dysplasia fetuses [J].
Delezoide, AL ;
LasselinBenoist, C ;
LegeaiMallet, L ;
Brice, P ;
Senee, V ;
Yayon, A ;
Munnich, A ;
Vekemans, M ;
Bonaventure, J .
HUMAN MOLECULAR GENETICS, 1997, 6 (11) :1899-1906
[7]   Fibroblast growth factor receptor 3 is a negative regulator of bone growth [J].
Deng, CX ;
WynshawBoris, A ;
Zhou, F ;
Kuo, A ;
Leder, P .
CELL, 1996, 84 (06) :911-921
[8]   COMPLEXITY OF FGF RECEPTORS - GENETIC-BASIS FOR STRUCTURAL DIVERSITY AND FUNCTIONAL SPECIFICITY [J].
GIVOL, D ;
YAYON, A .
FASEB JOURNAL, 1992, 6 (15) :3362-3369
[9]   DIFFERENTIATION OF MUSCLE, FAT, CARTILAGE, AND BONE FROM PROGENITOR CELLS PRESENT IN A BONE-DERIVED CLONAL CELL-POPULATION - EFFECT OF DEXAMETHASONE [J].
GRIGORIADIS, AE ;
HEERSCHE, JNM ;
AUBIN, JE .
JOURNAL OF CELL BIOLOGY, 1988, 106 (06) :2139-2151
[10]  
HORTON WA, 1993, PROG CLIN BIOL RES, V383, P533