Fibroblast growth factor receptor 1 (FGFR-1), also known as basic fibroblast growth factor receptor 1, fms-related tyrosine kinase-2 / Pfeiffer syndrome, and CD331, is a receptor tyrosine kinase whose ligands are specific members of the fibroblast growth factor family. FGFR-1 has been shown to be associated with Pfeiffer syndrome, and clonal eosinophilias.
Gene The FGFR1 gene is located on human chromosome 8 at position p11.23 (i.e. 8p11.23), has 24 exons, and codes for a Precursor mRNA that is alternatively spliced at exons 8A or 8B thereby generating two mRNAs coding for two FGFR1 isoforms, FGFR1-IIIb (also termed FGFR1b) and FGFR1-IIIc (also termed FGFR1c), respectively. Although these two isoforms have different tissue distributions and FGF-binding affinities, FGFR1-IIIc appears responsible for most of functions of the FGFR1 gene while FGFR1-IIIb appears to have only a minor, somewhat redundant functional role. There are four other members of the FGFR1 gene family: FGFR2, FGFR3, FGFR4, and Fibroblast growth factor receptor-like 1 (FGFRL1). The FGFR1 gene, similar to the FGFR2-4 genes are commonly activated in human cancers as a result of their duplication, fusion with other genes, and point mutation; they are therefore classified as proto-oncogenes.
Protein Receptor FGFR1 is a member of the fibroblast growth factor receptor (FGFR) family, which in addition to FGFR1, includes FGFR2, FGFR3, FGFR4, and FGFRL1. FGFR1-4 are cell surface membrane receptors that possess tyrosine kinase activity. A full-length representative of these four receptors consists of an extracellular region composed of three immunoglobulin-like domains which bind their proper ligands, the fibroblast growth factors (FGFs), a single hydrophobic stretch which passes through the cell's surface membrane, and a cytoplasmic tyrosine kinase domain. When bonded to FGFs, these receptors form dimers with any one of the four other FGFRs and then cross-phosphorylate key tyrosine residues on their dimer partners. These newly phosphorylated sites bind cytosolic docking proteins such as FRS2, PRKCG and GRB2 which proceed to activate cell signaling pathways that lead to cellular differentiation, growth, proliferation, prolonged survival, migration, and other functions. FGFRL1 lacks a prominent intracellular domain and tyrosine kinase activity; it may serve as a decoy receptor by binding with and thereby diluting the action of FGFs. There are 18 known FGFs that bind to and activate one or more of the FGFRs: FGF1 to FGF10 and FGF16 to FGF23. Fourteen of these, FGF1 to FGF6, FGF8, FGF10, FGF17, and FGF19 to FGF23 bind and activate FGFR1. FGFs binding to FGFR1 is promoted by their interaction with cell surface heparan sulfate proteoglycans and, with respect to FGF19, FGF20, and FGR23, the transmembrane protein Klotho.
Cell activation FGFR1, when bound to a proper FGF, elicits cellular responses by activating signaling pathways that include the: a) Phospholipase C/PI3K/AKT, b) Ras subfamily/ERK, c) Protein kinase C, d) IP3-induced raising of cytosolic Ca2+, and e) Ca2+/calmodulin-activated elements and pathways. The exact pathways and elements activated depend on the cell type being stimulated plus other factors such as the stimulated cells microenvironment and previous as well as concurrent history of stimulation
Activation of the gamma isoforms of phospholipase C (PLCγ) (see PLCG1 and PLCG2 illustrates one mechanism by which FGFR1 activates cell stimulating pathways. Following its binding of a proper FGF and subsequent pairing with another FGFR, FGFR1 becomes phosphorylated by its partner FGFR on a highly conserved tyrosine residue (Y766) at its C-terminal. This creates a binding or "docking" site to recruit PLCγ via PLCγ tandem nSH2 and cSH2 domains and then phosphorylate PLCγ. By being phosphorylated PLCγ is relieved of its auto-inhibition structure and becomes active in metabolizing nearby phosphatidylinositol 4,5-bisphosphate to two secondary messengers, inositol trisphosphate (IP3) and diacyglycerol (DAG). These secondary messengers proceed to mobilize other cell-signaling and cell-activating agents: IP3 elevates cytosolic Ca2+ and thereby various Ca2+-sensitive elements while DAG activates various protein kinase C isoforms.
Recent publication on the 2.5 Å crystal structure of PLCγ in complex with FGFR1 kinase (PDB: 3GQI) provides new insights in understanding the molecular mechanism of FGFR1's recruitment of PLCγ by its SH2 domains. Figure 1 on the extreme right shows the PLCγ-FGFR1 kinase complex with the c-SH2 domain colored in red, n-SH2 domain colored in blue, and the interdomain linker colored in yellow. The structure contains typical SH2 domain, with two α-helices and three antiparallel β-strands in each SH2 domain. In this complex, the phosphorylated tyrosine (pY766) on the C-terminal tail of FGFR1 kinase binds preferentially to the nSH2 domain of PLCγ. The phosphorylation of tyrosine residue 766 on FGFR1 kinase forms hydrogen bonds with the n-SH2 to stabilize the complex. Hydrogen bonds in the binding pocket help to stabilize the PLCγ-FGFR1 kinase complex. The water molecule as shown mediates the interaction of asparagine 647 (N647) and aspartate 768 (D768) to further increase the binding affinity of the n-SH2 and FGFR1 kinase complex. (Figure 2). The phosphorylation of tyrosine 653 and tyrosine 654 in the active kinase conformation causes a large conformation change in the activation segment of FGFR1 kinase. Threonine 658 is moved by 24Å from the inactive form (Figure 3.) to the activated form of FGFR1 kinase (Figure 4.). The movement causes the closed conformation in the inactive form to open to enable substrate binding. It also allows the open conformation to coordinate Mg2+ with AMP-PCP (analog of ATP). In addition, pY653 and pY654 in the active form helps to maintain the open conformation of the SH2 and FGFR1 kinase complex. However, the mechanism by which the phosphorylation at Y653 and Y654 helps to recruit the SH2 domain to its C-terminal tail upon phosphorylation of Y766 remains elusive. Figure 5 shows the overlay structure of active and inactive forms of FGFR1 kinase. Figure 6 shows the dots and contacts on phosphorylated tyrosine residues 653 and 654. Green dots show highly favorable contacts between pY653 and pY654 with surrounding residues. Red spikes show unfavorable contacts in the activation segment. The figure is generated through Molprobity extension on Pymol.
The tyrosine kinase region of FGFR1 binds to the N-SH2 domain of PLCγ primarily through charged amino acids. Arginine residue (R609) on the N-SH2 domain forms a salt bridge to aspartate 755 (D755) on the FGFR1 domain. The acid base pairs located in the middle of the interface are nearly parallel to each other, indicating a highly favorable interaction. The N-SH2 domain makes an additional polar contact through water-mediated interaction that takes place between the N-SH2 domain and the FGFR1 kinase region. The arginine residue 609 (R609) on the FGFR1 kinase also forms a salt bridge to the aspartate residue (D594) on the N-SH2 domain. The acid-base pair interacts with each other carry out a reduction–oxidation reaction that stabilizes the complex (Figure 7). Previous studies have done to elucidate the binding affinity of the n-SH2 domain with the FGFR1 kinase complex by mutating these phenylalanine or valine amino acids. The results from isothermal titration calorimetry indicated that the binding affinity of the complex decreased by 3 to 6-fold, without affecting the phosphorylation of the tyrosine residues.
Cell inhibition FGF-induced activation of FGFR1 also stimulates the activation of sprouty proteins SPRY1, SPRY2, SPRY3, and/or SPRY4 which in turn interact with GRB2, SOS1, and/or c-Raf to reduce or inhibit further cell stimulation by activated FGFR1 as well as other tyrosine kinase receptors such as the Epidermal growth factor receptor. These interactions serve as negative feedback loops to limit the extent of cellular activation.
Function Mice genetically engineered to lack a functional Fgfr1 gene (ortholog of the human FGFR1 gene) die in utero before 10.5 days of gestation. Embryos exhibit extensive deficiencies in the development and organization of mesoderm-derived tissues and the musculoskeletal system. The Fgfr1 gene appears critical for the truncation of embryonic structures and formation of muscle and bone tissues and thereby the normal formation of limbs, skull, outer, middle, and inner ear, neural tube, tail, and lower spine as well as normal hearing.
Clinical significance Congenital diseases Hereditary mutations in the FGFR1 gene are associated with various congenital malformations of the musculoskeletal system. Interstitial deletions at human chromosome 8p12-p11, arginine to a stop nonsense mutation at FGFR1 amino acid 622 (annotated as R622X), and numerous other autosomal dominant inactivating mutations in FGFR1 are responsible for ~10% of the cases of Kallmann syndrome. This syndrome is a form of hypogonadotropic hypogonadism associated in a varying percentage of cases with anosmia or hyposmia; cleft palate and other craniofacial defects; and scoliosis and other musculoskeletal malformations. An activating mutation in FGFR1 viz., P232R (proline-to-arginine substitution in the protein's 232nd amino acid), is responsible for the Type 1 or classic form of Pfeiffer syndrome, a disease characterized by craniosynostosis and mid-face deformities. A tyrosine-to-cysteine substitution mutation in the 372nd amino acid of FGFR1 (Y372C) is responsible for some cases of Osteoglophonic dysplasia. This mutation results in craniosynostosis, mandibular prognathism, hypertelorism, brachydactyly, and inter-phalangeal joint fusion. Other inherited defects associated with 'FGFR1 mutations likewise involve musculoskeletal malformations: these include the Jackson–Weiss syndrome (proline to arg substitution at amino acid 252), Antley-Bixler syndrome (isoleucine-to-threonine at amino acid 300 (I300T), and trigonocephaly (mutation the same as the one for the Antley-Bixler syndrome viz., I300T).
Cancers
Somatic mutations and epigenetic changes in the expression of the FGFR1 gene occur in and are thought to contribute to various types of lung, breast, hematological, and other types of cancers.
Lung cancers Amplification of the FGFR1 gene (four or more copies) is present in 9 to 22% of patients with non-small-cell lung carcinoma (NSCLC). FGFR1 amplification was highly correlated with a history of tobacco smoking and proved to be the single largest prognostic factor in a cohort of patients suffering this disease. About 1% of patients with other types of lung cancer show amplifications in FGFR1.
Breast cancers Amplification of FGFR1 also occurs in ~10% of estrogen receptor positive breast cancers, particularly of the luminal subtype B form of breast cancer. The presence of FGFR1 amplification has been correlated with resistance to hormone blocking therapy and found to be a poor prognostic factor in the disease.
Hematological cancers