Characterization of FGFRL1, a Novel Fibroblast Growth Factor (FGF) Receptor Preferentially Expressed in Skeletal Tissues

Abstract

Clones for a novel transmembrane receptor termed FGFRL1 were isolated from a subtracted, cartilage-specific cDNA library prepared from chicken sterna. Homologous sequences were identified in other vertebrates, including man, mouse, rat and fish, but not in invertebrates such as Caenorhabditis elegans and Drosophila. FGFRL1 was expressed preferentially in skeletal tissues as demonstrated by Northern blotting and in situ hybridization. Small amounts of the FGFRL1 mRNA were also detected in other tissues such as skeletal muscle and heart. The novel protein contained three extracellular Ig-like domains that were related to the members of the fibroblast growth factor (FGF) receptor family. However, it lacked the intracellular protein tyrosine kinase domain required for signal transduction by transphosphorylation. When expressed in cultured cells as a fusion protein with green fluorescent protein, FGFRL1 was specifically localized to the plasma membrane where it might interact with FGF ligands. Recombinant FGFRL1 protein was produced in a baculovirus system with intact disulfide bonds. Similar to FGF receptors, the expressed protein interacted specifically with heparin and with FGF2. When overexpressed in MG-63 osteosarcoma cells, the novel receptor had a negative effect on cell proliferation. Taken together our data are consistent with the view that FGFRL1 acts as a decoy receptor for FGF ligands.Most bones of the vertebrate skeleton are formed by a complex process termed endochondral ossification which involves a cartilage intermediate (1). This intermediate represents a highly specialized connective tissue. It consists of a single cell type, the chondrocytes, which are embedded in a rich extracellular matrix (2). Typically, this matrix makes up more than 90% of the cartilage volume and consists of collagens (types II, IX, X, and XI), proteoglycans (aggrecan, small leucine-rich proteins), and glycoproteins (matrilins, COMP).During the first step of endochondral ossification, mesenchymal cells condense and differentiate into chondrocytes (3). These chondrocytes proliferate rapidly and lay down the cartilaginous model of the future bones. The chondrocytes undergo a complex series of distinct developmental stages, including proliferation, maturation, and hypertrophy. The hypertrophic cartilage is calcified and becomes vascularized. Finally, the calcified cartilage is invaded by osteoclasts and osteoblasts, which replace the cartilaginous tissue by bone.Cartilage has become a popular tissue to study cell proliferation and differentiation in vitro (3). When cultivated on plastic dishes, chondrocytes rapidly dedifferentiate into fibroblast-like cells. In three-dimensional lattices, however, the chondrocytes undergo the ordered sequence of events observed during differentiation and maturation of cartilage in vivo. Three stages of chondrocyte differentiation have been defined in vitro: proliferative chondrocytes producing mainly collagen II, hypertrophic chondrocytes producing collagen X, and osteoblast-like cells producing...

Fibroblast Growth Factor Receptor Like-1 (FGFRL1) Interacts with SHP-1 Phosphatase at Insulin Secretory Granules and Induces Beta-cell ERK1/2 Protein Activation

“…has been postulated to act as a decoy receptor due to ligand binding ability and the absence of a C-terminal tyrosine kinase domain (11,12,32). To explore the effect of FGFRL1 on beta-cell MAPK signaling activity, we examined ERK1/2 phosphorylation in ␤TC3 cells stably expressing the full-length (RL1) and truncated (RL1-⌬His and RL1-⌬C) receptor constructs (Fig.…”

“…FGFLR1 Associates with Insulin Secretory Granules and Late Endosomes-Previous work has revealed that FGFRL1 localizes to secretory granules in HEK293 cells, a kidney cell line (31,32). To determine FGFRL1 localization in ␤TC3 cells, we co-expressed the full-length (RL1) and truncated (RL1-⌬His and RL1-⌬C) constructs with Phogrin eGFP , a marker for insulin secretory granules, and Rab7 eGFP , a marker for late recycling endosomes (Fig.…”

Wolf–Hirschhorn syndrome facial dysmorphic features in a patient with a terminal 4p16.3 deletion telomeric to the WHSCR and WHSCR 2 regions

“…11,12 The FGFRL1 gene shows particularly pronounced expression in the primordia of bones (eg, the maxillae, the mandibles, the ribs and the nose) and in the permanently cartilaginous tissues of the trachea. Although the muscle of the tongue and the diaphragm express FGFRL1 at a relatively high level, the heart, skeletal muscle, brain, lung, liver, kidney and gut express FGFRL1 at a basal level.…”

Role of fibroblast growth factors in pancreatic cancer

“…Ген Fgf15 мыши имеет человеческий ортолог -ген FGF19, который кодирует белок FGF19, соответствующий Fgf15 мыши, поэтому их называют FGF15/19. В зависимости от функциональных свойств все факторы FGF делят на несколько подсемейств: паракринные (1-10, 16-20, 22); эндокринные, или гормоноподобные (15,19,21,23); и интракринные (11)(12)(13)(14). Секретируемые белки FGF способны индуцировать физиологический эффект в расположенных вблизи клетках-мишенях (паракринные FGF), а также оказывать системное влияние на отдалённые ткани и органы (эндокринные FGF).…”

“…С недавнего времени выделяют FGFR5, или FGFRL1, сходный с другими FGFR по аминокислотной последовательности, но, по-видимому, не являющийся самостоятельным рецептором, поскольку он не имеет цитоплазматического тирозинкиназного домена, и передача сигнала происходит непрямым путём через FGFR1 [12][13][14] сигнальных путей: PLCg, STAT, FSR2-зависимых Ras/MAPK и PI3K/Akt (рис. 1а).…”