FRAG1, a Gene that Potently Activates Fibroblast Growth Factor Receptor by C-Terminal Fusion through Chromosomal Rearrangement

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 17; pp. 8956 - 8961
• Main Authors: Lorenzi, Matthew V., Horii, Yoshihiro, Yamanaka, Ryuya, Sakaguchi, Kazushige, Miki, Toru
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 20.08.1996; National Acad Sciences
• Subjects: 3T3 Cells; Amino Acid Sequence; Amino acids; Animals; Antibodies; Base Sequence; Binding Sites; Cell Compartmentation; Cell lines; Chromosome Aberrations; Cloning, Molecular; Complementary DNA; Gene Rearrangement; Genes; Mice; Molecular Sequence Data; Mutation; NIH 3T3 cells; Nuclear Proteins - genetics; Nuclear Proteins - isolation & purification; Nuclear Proteins - metabolism; Protein Conformation; Protein isoforms; Proteins; Rats; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Fibroblast Growth Factor, Type 2; Receptors; Receptors, Fibroblast Growth Factor - genetics; Receptors, Fibroblast Growth Factor - metabolism; Sequence Analysis, DNA; Sequence Deletion; Sequence Homology, Amino Acid; Signal Transduction; Tumor Cells, Cultured
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.17.8956

A constitutively active form of fibroblast growth factor 2 (FGFR2) was identified in rat osteosarcoma (ROS) cells by an expression cloning strategy. Unlike other tyrosine kinase receptors activated by N-terminal truncation in tumors, this receptor, FGFR2-ROS, contains an altered C terminus generated from chromosomal rearrangements with a novel gene, designated FGFR activating gene 1 (FRAG1). While the removal of the C terminus slightly activates FGFR2, the presence of the FRAG1 sequence drastically stimulates the transforming activity and autophosphorylation of the receptor. FGFR2-ROS is expressed as a unusually large protein and is highly phosphorylated in NIH 3T3 transfectants. FRAG1 is ubiquitously expressed and encodes a predicted protein of 28 kDa lacking significant structural similarity to known proteins. Epitope-tagged FRAG1 protein showed a perinuclear localization by immunofluorescence staining. The highly activated state of FGFR2-ROS appears to be attributed to constitutive dimer formation and higher phosphorylation level as well as possibly altered subcellular localization. These results indicate a unique mechanism of receptor activation by a C terminus alteration through a chromosomal fusion with FRAG1.