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The Ser252Trp fibroblast growth factor receptor-2 (FGFR-2) mutation induces PKC-independent downregulation of FGFR-2 associated with premature calvaria osteoblast differentiation.
Exp Cell Res. 2000 Apr 10; 256(1):158-67.EC

Abstract

We recently showed that the Apert Ser252Trp fibroblast growth factor receptor-2 (FGFR-2) mutation causes premature osteoblast differentiation and increased subperiosteal calvaria bone matrix formation. To gain further insight into the cellular mechanisms involved in these effects, we examined the effects of the mutation on the expression of FGFRs in relation to cell proliferation and differentiation markers in vivo and in vitro, and we analyzed the underlying signaling pathways in mutant cells. Immunohistochemical analysis of the Apert calvaria suture showed that the Ser252Trp FGFR-2 mutation increased type 1 collagen, osteocalcin, and osteopontin expression in preosteoblasts compared to normal, whereas cell growth was not affected. The premature osteoblast differentiation induced by the mutation was associated with lower than normal FGFR-2 immunolabeling, whereas FGFR-1 and FGFR-3 levels were not decreased. Immunocytochemical analysis in osteoblasts isolated from Apert coronal suture showed that the Ser252Trp mutation induced constitutive downregulation of FGFR-2 in mutant cells. Western blot analysis of FGFRs in immortalized mutant osteoblastic cells confirmed that the mutation induced FGFR-2 downregulation. FGFR-2 mRNA levels were not altered in mutant cells, indicating that FGFR-2 downregulation resulted from receptor internalization rather than from changes in receptor mRNA. The signaling pathway involved in FGFR-2 downregulation was studied using specific inhibitors of FGF signaling molecules. The selective PKC inhibitor calphostin C markedly reduced FGFR-2 protein levels in mutant cells, in contrast to the p38 MAP kinase inhibitor SB 203580 or the Erk 1,2 MAP kinase inhibitor PD-98059, showing that PKC is involved in FGFR-2 regulation, but not in FGFR-2 downregulation in mutant cells. The results indicate that the premature osteoblast differentiation induced by the FGFR-2 Ser252Trp mutation is associated with a PKC-independent downregulation of FGFR-2 in human calvaria cells.

Authors+Show Affiliations

Unit 349 INSERM Affiliated to CNRS, Lariboisière Hospital, Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10739663

Citation

Lemonnier, J, et al. "The Ser252Trp Fibroblast Growth Factor Receptor-2 (FGFR-2) Mutation Induces PKC-independent Downregulation of FGFR-2 Associated With Premature Calvaria Osteoblast Differentiation." Experimental Cell Research, vol. 256, no. 1, 2000, pp. 158-67.
Lemonnier J, Delannoy P, Hott M, et al. The Ser252Trp fibroblast growth factor receptor-2 (FGFR-2) mutation induces PKC-independent downregulation of FGFR-2 associated with premature calvaria osteoblast differentiation. Exp Cell Res. 2000;256(1):158-67.
Lemonnier, J., Delannoy, P., Hott, M., Lomri, A., Modrowski, D., & Marie, P. J. (2000). The Ser252Trp fibroblast growth factor receptor-2 (FGFR-2) mutation induces PKC-independent downregulation of FGFR-2 associated with premature calvaria osteoblast differentiation. Experimental Cell Research, 256(1), 158-67.
Lemonnier J, et al. The Ser252Trp Fibroblast Growth Factor Receptor-2 (FGFR-2) Mutation Induces PKC-independent Downregulation of FGFR-2 Associated With Premature Calvaria Osteoblast Differentiation. Exp Cell Res. 2000 Apr 10;256(1):158-67. PubMed PMID: 10739663.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Ser252Trp fibroblast growth factor receptor-2 (FGFR-2) mutation induces PKC-independent downregulation of FGFR-2 associated with premature calvaria osteoblast differentiation. AU - Lemonnier,J, AU - Delannoy,P, AU - Hott,M, AU - Lomri,A, AU - Modrowski,D, AU - Marie,P J, PY - 2000/3/31/pubmed PY - 2000/5/20/medline PY - 2000/3/31/entrez SP - 158 EP - 67 JF - Experimental cell research JO - Exp. Cell Res. VL - 256 IS - 1 N2 - We recently showed that the Apert Ser252Trp fibroblast growth factor receptor-2 (FGFR-2) mutation causes premature osteoblast differentiation and increased subperiosteal calvaria bone matrix formation. To gain further insight into the cellular mechanisms involved in these effects, we examined the effects of the mutation on the expression of FGFRs in relation to cell proliferation and differentiation markers in vivo and in vitro, and we analyzed the underlying signaling pathways in mutant cells. Immunohistochemical analysis of the Apert calvaria suture showed that the Ser252Trp FGFR-2 mutation increased type 1 collagen, osteocalcin, and osteopontin expression in preosteoblasts compared to normal, whereas cell growth was not affected. The premature osteoblast differentiation induced by the mutation was associated with lower than normal FGFR-2 immunolabeling, whereas FGFR-1 and FGFR-3 levels were not decreased. Immunocytochemical analysis in osteoblasts isolated from Apert coronal suture showed that the Ser252Trp mutation induced constitutive downregulation of FGFR-2 in mutant cells. Western blot analysis of FGFRs in immortalized mutant osteoblastic cells confirmed that the mutation induced FGFR-2 downregulation. FGFR-2 mRNA levels were not altered in mutant cells, indicating that FGFR-2 downregulation resulted from receptor internalization rather than from changes in receptor mRNA. The signaling pathway involved in FGFR-2 downregulation was studied using specific inhibitors of FGF signaling molecules. The selective PKC inhibitor calphostin C markedly reduced FGFR-2 protein levels in mutant cells, in contrast to the p38 MAP kinase inhibitor SB 203580 or the Erk 1,2 MAP kinase inhibitor PD-98059, showing that PKC is involved in FGFR-2 regulation, but not in FGFR-2 downregulation in mutant cells. The results indicate that the premature osteoblast differentiation induced by the FGFR-2 Ser252Trp mutation is associated with a PKC-independent downregulation of FGFR-2 in human calvaria cells. SN - 0014-4827 UR - https://www.unboundmedicine.com/medline/citation/10739663/The_Ser252Trp_fibroblast_growth_factor_receptor_2__FGFR_2__mutation_induces_PKC_independent_downregulation_of_FGFR_2_associated_with_premature_calvaria_osteoblast_differentiation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4827(00)94820-1 DB - PRIME DP - Unbound Medicine ER -