Ligand-independent activation of fibroblast growth factor receptor-2 by carboxyl terminal alterations

• Published in: Oncogene Vol. 15; no. 7; pp. 817 - 826
• Main Authors: LORENZI, M. V, CASTAGNINO, P, CHEN, Q, CHEDID, M, MIKI, T
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 14.08.1997; Nature Publishing Group
• Subjects: 3T3 Cells; Animals; Biological and medical sciences; C-Terminus; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell activation; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Colony-Forming Units Assay; Extracellular signal-regulated kinase; Fibroblast growth factor receptor 2; Fundamental and applied biological sciences. Psychology; H-Ras protein; Humans; Kinases; Ligands; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Molecular and cellular biology; Molecular Sequence Data; mRNA; Mutants; Peptide Fragments - genetics; Peptide Fragments - physiology; Phosphorylation; Point Mutation; Protein kinase; Protein-Tyrosine Kinases - metabolism; Receptor mechanisms; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptor Protein-Tyrosine Kinases - physiology; Receptor, Fibroblast Growth Factor, Type 2; Receptors, Fibroblast Growth Factor - genetics; Receptors, Fibroblast Growth Factor - metabolism; Receptors, Fibroblast Growth Factor - physiology; RNA, Messenger - metabolism; Sequence Deletion; Transfection; Transformed cells; Tumor cell lines; Tumor Cells, Cultured; Tumors; Tyrosine - genetics; Tyrosine - physiology; Fibroblast growth factor; Enzyme; Transferases; Rodentia; Activation; Gene expression; Cell transformation; C terminal-Sequence; Vertebrata; Membrane receptor; Regulation(control); Mammalia; Cell line; Gene; Mouse; Polypeptide; Mutation; Protein-tyrosine kinase; Growth factor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1201242

To assess the effect(s) of the C-terminal domain on FGFR2 function, we engineered a series of mutant FGFR2 cDNAs encoding deletions in the C-terminus of the receptor and compared their growth properties in NIH3T3 fibroblasts. In contrast to FGFR2-WT, receptors with C-terminal truncations induced ligand-independent transformation of NIH3T3 cells and transfectants expressing these mutant receptors efficiently formed colonies in semisolid medium. Introduction of point mutations (Y to F) into the C-terminus of FGFR2 at positions 813, 784 or 780 revealed that these mutant receptors also displayed activities similar to that of C-terminally truncated receptors. C-terminally altered FGF receptors did not show an increase in the basal level of receptor phosphorylation compared to that of FGFR2-WT suggesting that elevated receptor phosphorylation does not underlie the transforming activity of these receptors. Interestingly, expression of transforming FGFR2 derivatives, unlike H-Ras transformed cells, did not result in the activation of the mitogen-activated protein kinases (MAPKs), p42/ERK2 and p44/ERK1, indicating that this pathway is not constitutively active in FGFR2-transformed cells. Finally, we report the overexpression of FGFR2 mRNA and protein in several human tumor cell lines suggesting activation of the receptor in these tumors.