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Atlas Genet Cytogenet Oncol Haematol. 2009; 13(11) 821

Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL AT INIST-CNRS

FGFR1 (Fibroblast Growth Factor Receptor 1) Jean-Loup Huret

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: December 2008

Online updated version : http://AtlasGeneticsOncology.org/Genes/FGFR1113.html DOI: 10.4267/2042/44609

This article is an update of : Pébusque MJ. FGFR1 (Fibroblast Growth Factor Receptor 1). Atlas Genet Cytogenet Oncol Haematol 2001;5(1):9-10 HuretJL. FGFR1 (Fibroblast Growth Factor Receptor 1). Atlas Genet Cytogenet Oncol Haematol 1998;2(2):35 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: BFGFR (basic fibroblast growth factor receptor); FLT2 (FMS-like tyrosine kinase 2); FGFBR (FGFb receptor); FLG (FMS-like gene); CEK (chicken embryo kinase); CD331 (CD331 antigen); H2 (heparin-binding growth factor receptor); KAL2 (Kallmann); N-SAM (NCC-IT-cell derived stomach cancer amplified gene)

HGNC (Hugo): FGFR1

Location: 8p12

DNA/RNA

FGFR1 (8p12) - Courtesy Mariano Rocchi, Resources for

Molecular Cytogenetics.

Fig 1. FGFR1 (8p12) gene and protein. FGFR1 comprises an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain contains a signal peptide (SP), two (IgII, IgIII) or three (IgI, IgII, and IgIII) Ig-like domains; it is followed by the transmembrane domain (TM), and an intracellular domain comprising a juxtamembrane domain (JM), two tyrosine kinase subdomains (TK1,TK2) interrupted by a short kinase insert (KI), and a C-terminal tail (CT). The acidic box (AB) indicated in the extracellular domain is a specific feature of FGF receptors; a CHD (cell adhesion molecule (CAM) homogogy domain) and a HB domain (binding domain for heparin or heparin sulfate proteoglycan HSPG) are present in the extracellular part. A NB (nuclear binding domain), and the PLC site (interaction with PLC gamma) are found in the cytosolic part of FGFR1.

FGFR1 (Fibroblast Growth Factor Receptor 1) Huret JL


Fig 2. FGFR1 splice forms. Showing soluble forms (A, B) and membrane-attached forms (C, D, E); forms IIIa (B), IIIb (C), and IIIc (D, E), according to the 3' part of the third Ig-like domain; forms alpha (C, D) with 3 Ig-like domains, and beta (E), with only 2. Exons are shown on the top right (forms a, b, c, d, and e). Adapted from Johnson and Williams 1993, and SpliceCenter data.

Description The DNA has been cloned in 1989 (Lee et al., 1989).

Transcription The gene spans 57,697 bases on reverse strand; there are numerous splicing forms, with mRNAs from about 3 kb to 5.688 kb for the canonical form, made of 18 exons. 11 transcripts for Ensembl, 18 transcripts for Swiss-Prot. Different transcripts are expressed in different cells and tissues. Some isoforms are truncated in the extracellular domain (IgI, in particular, is often missing), others in the intracellular domain (TK2 missing) or both. Secreted forms lack the transmembrane domain; TK truncated forms are kinase-deficient. Exon numbering is variable.

Protein Description The canonical form comprises 822 amino acids; 100-135 kDa glycoprotein from a 90-115 kDa protein core. FGFR1 is composed of an extracellular ligand-binding domain, a unique transmembrane domain, and a catalytic (tyrosine kinase) cytosolic domain. The extracellular region (with the N-terminus) contains a signal peptide (amino acids (aa) 1-21), 3 immunoglobulin-like loops (aa: 25-119, 158-246, and 255-357 according to Swiss-Prot), with an acidic box (seven glutamic acids in 127-133) between IgI and IgII, a CHD (Cell adhesion molecule (CAM) homogogy domain) in 151-170, and an heparin-binding domain in

the begining of the IgII (aa 166-177); this extracellular region is followed by a transmembrane domain (aa 377-397) and an intracellular domain composed of a juxtamembrane domain, which serves as a binding site for phosphotyrosine binding (PTB) domains of proteins such as FRS2 (see below), and a tyrosine kinase domain (aa 478-767) (two kinase domains interrupted by a short kinase insert of 14 amino acids), and a C-terminal tail. A part of the C-terminal tail of FGFR1 containing 28 amino acids binds the SH2 domain of PLCG (PLC gamma). Phosphorylation of Tyrosine 766 is the interactive item with PLC gamma (Itoh et al., 1990; Johnson and Williams, 1993) (Fig 1). A triad of residues N546, E562, and K638 would form a network of hydrogen bounds acting as a molecular brake keeping the kinase in an autoinhibited state (Chen et al., 2007). Details on crystal structure can be found in Eswarakumar et al., 2005. The five tyrosine autophosphorylation sites in the catalytic core of FGFR1 are phosphorylated by a precisely controlled and ordered reaction. The rate of catalysis of two substrates is enhanced by 50- and 500-fold after autophosphorylation of Y653 and Y654, respectively, in the activation loop of FGFR1 (Furdui et al., 2006).

FGFR1 splice variants - isoforms Soluble forms/forms without TK activity: Splice variants generate isoforms with different ligand-binding specificities, and differently expressed in different cells and tissues. Some isoforms are truncated in the extracellular domain, lacking Ig-like domains, other in the intracellular domain, lacking the kinase



domain, or both. They are soluble forms if the transmembrane domain is missing. However, if soluble forms can result from variant splicing, they can also result from proteolytic cleavage (Groth and Lardelli, 2002). A short transcript ending 32 amino acids after the first Ig-like domain (See Fig 2A) has been found. It is reminiscent of similar forms of N-CAM (Johnson and Williams, 1993). Variants lacking parts of the TK domain(s) may act as down regulators of the signal, since they can heterodimerize with active forms, leading to non-functionnal dimer receptors. FGFR1 IIIa/ FGFR1 IIIb/ FGFR1 IIIc: Three possible variants of Ig-like domain III are known for FGFR1, FGFR2, and FGFR3 (Johnson et al., 1991). FGFR1 IIIa (Fig 2B) ends downstream of IgIII-like domain. It is a secreted receptor devoid of signaling capacity. It is expressed in adult tissues and in cell lines. It may be essential during mesoderm induction. FGFR1 IIIa binds FGF2 with a higher affinity than FGF1, contrarity to FGFR IIIb. FGFR IIIc binds both with equal affinity. FGFR1 IIIb (Fig 2C) is expressed in epithelial lineages, FGFR1 IIIc (Fig 2D and E; compare the exons with form IIIb) in mesenchymal lineages. FGFR1 IIIc is also preferentially expressed in cell lines. Whereas FGFR1 IIIc was found expressed in nearly all tissues examined, FGFR1 IIIa was found expresssed in brain, muscle and skin, and FGFR IIIb in skin, brain, kidney, muscle and placenta (Johnson and Williams, 1993). Changes in FGFR isoform expression seem to regulate tumorigenesis and malignant transformation (Liu et al., 2007). Targeted disruption of FGFR1 IIIc provoked mouse embryo lethality due to a defect in cell migration through the primitive streack, whereas FGFR1 IIIb deficient mouse embryo showed no obvious defect (reviewed in Eswarakumar et al., 2005). FGFR1alpha/FGFR1beta: FGFR1 IIIb and FGFR1 IIIc can have 3 Ig-like domains (called FGFR1alpha), or, in case IgI (encoded by exon 3, also called "the alpha-exon") is deleted by splicing, only 2 Ig like domains (FGFR1beta) (ex Fig 2D versus 2E). Two intronic silencing sequence (ISS) elements flank the alternatively spliced alpha-exon. These ISS appear to regulate the alpha-exon exclusion. The splicing is at least partly regulated by SFPQ (1p34, splicing factor proline/glutamine-rich). Note on SFPQ: see the glioblastoma section herein below. Almost all tissues contain both forms of FGFR1. The first Ig domain may be deleted without ligand binding consequence. However, it's splicing is tissue-dependant: the FGFR1 with 3 Ig like domains (FGFR1alpha) is predominant during mouse embryogenesis, while the form with only 2 Ig like domains (FGFR1beta) is equally expressed after birth in most tissues. FGFR1beta exhibits a 10-fold higher affinity for FGF1 and FGF2 than FGFR1alpha. Only FGFR1alpha has been found in the nucleus.

Aberrant splicing of the alpha-exon has been associated with pancreatic cancer, breast cancer, and glioblastoma (Bruno et al., 2004).

Receptor specificity FGFs (fibroblast growth factors): The various FGFR1 isoforms have different affinities for FGFs (Table 1); however, the only FGFs that FGFR1 binds with high affinity are FGF1 (alias aFGF: acidic FGF) and FGF2 (alias bFGF: basic FGF). Heparan sulfate proteoglycans (HSPG) may play an important role in the modulation of the different FGFs binding affinities. HSPG are polysaccharides with various additions of sulfate groups which may be critical for FGF-FGFRs affinities (Fig 3). In a given cell at a given state of proliferation/differentiation, a given HSPG would favour a given FGF-FGFR binding and signaling. TABLE I: FGFs and targets FGFRs (from Zang et al., 2006)

FGF subfamilies FGF FGFR

FGF1 (secreted or intracellular)

FGF1

FGF2

all FGFRs

FGFR 1c, 3c > 2c, 1b, 4∆

FGF4 (secreted) FGF4, FGF5, FGF6

FGFR 1c, 2c > 3c, 4∆

FGF7 (secreted)

FGF3, FGF7, FGF10, FGF22

FGFR 2b > 1b


FGFR 3c > 4∆, > 2c > 1c > 3b


FGFR 3c > 2c > 1c, 3b > 4∆


FGFR 1c, 2c, 3c, 4∆ (weak)

FGF11 (intracellular)

FGF11, FGF12, FGF13, FGF14

Not known

Cell adhesion molecules: FGFR1 possesses a CHD (Cell adhesion molecule (CAM) homology domain). Cell adhesion molecules L1CAM (Xq28; L1 cell adhesion molecule), NCAM1 and NCAM2 (11q23 and 21q21; neural cell adhesion molecules) and the members of the vast cadherin family are transmembrane receptors that maintain adhesion between epithelial cells. FGF1 and FGF2 induce the internalization of surface FGFR1 and surface CDH1 (16q22; alias E-cadherin) in an endosome before



nuclear import into the nucleus (Bryant et al., 2005). CDH11 (16q21; cadherin 11) and FGFR1 can interact directly through their extracellular domains. The neuronal cell adhesion molecule L1CAM also interacts directly with FGFR1. L1CAM promotes axonal outgrowth through an interaction with FGFR1. The extracellular domain of L1CAM binds to the combined second and third Ig-like domains of FGFR1. Activation of FGFR1 is both necessary and sufficient to account for the ability of CAMs to stimulate axonal growth. PLC gamma (see below) is the downstream effector of this response (Doherty and Walsh, 1996; Saffell et al., 1997; Boscher and Mege, 2008; Kulahin et al., 2008).

Fig 3. FGF and FGFR1 signaling from the membrane: short version ... FGF, FGFR and heparan sulfate proteoglycans (HSPG) interact with each other, form a complex. Activation of the FGF-FGFR complex recruits FRS2, PTPN11, GRB2, SOS and GAB1, and also PLCG. The signal further implicates the RAS/RAF/MAPK pathway, the PI3K/AKT/mTOR pathway, the PLC gamma pathway, the JAK/STAT pathway, and the IKK/NF-KB pathway.

Expression FGFR1, 2 and 3 have distinct expresssion patterns but with overlaps in some tissues (Zhang et al., 2006). FGFR1 and FGFR2 exhibit broad expression in the embryo and latter in life, in contrast with other FGFRs. FGFR1 is predominantly expressed in the brain and in mesenchymal tissues in the embryo, in brain, bone, kidney, skin, lung, heart and muscle in the adulte, but

not in liver (Johnson and Williams, 1993) Note: expression of the various isoforms of FGFR1 is shortly described herein above.

Localisation Plasma membrane, indeed, but also cytosol and nucleus (see figure next page).

Function Shortly: Fibroblast growth factors receptors are a family of four receptor tyrosine kinases, named FGFR1 to 4. Each recognizes a unique subset of the fibroblast growth factors (FGF) family of ligands (Table 1). There are 22 FGF, from FGF1 to FGF23, with no FGF number 15 (see Ornitz and Itoh, 2001). The first family of FGFs consists of FGF1 and FGF2; they can either be secreted or remain intracellular (they possess a nuclear localization signal). The second and third families comprise FGF3-10 and 16-23 and are secreted; the last family (FGF11-14) remain intracellular, they do not bind FGFRs; they are called FHFs (FGF homologous factors). FGFs bind FGFRs to regulate cell growth, migration and differentiation during embryogenesis, and homeostasis later in life. They act both in mesenchymal and epithelial cells. The ligand-receptor complex, in association with heparin or heparan sulfate proteoglycan (FGF and FGFR both have heparan-binding sites), induces receptor dimerization. The FGFR1 signaling is achieved by receptor conformational changes upon ligand binding, leading to dimerization and subsequent activation by autophosphorylation of TK intracellular domains. It then activates the MAP (mitogen-activated protein) kinase pathway, necessary for cell cycle progression. However, FGFR1 dimerization leads to the activation of a number of other signaling molecules including the PI3K/AKT/mTOR pathway, the phospholipase Cgamma (PLCgamma) pathway, the JAK-STAT pathway, and, more indirectly, the IKK/NF-KB pathway (Fig 3). All these pathways interact with other, as is 'summarized' Figure 4. These functions depend on: 1- the expression of one or multiple FGF and FGF receptors, 2- the various and numerous splicings of the FGFR mRNA, 3- the cell and tissue involved (review in Naski and Ornitz, 1998; Ornitz and Itoh, 2001). FGF-FGFR binding Surface cell heparin or heparan sulfate proteoglycans (HSPG) interact with FGF to induce growth factor polymerization, binding to FGFR and subsequent dimerization of FGFRs. It is essential for the dimerization and activation of the FGF-FGFR complex.



Fig 4. FGF and FGFR1 signaling from the membrane AKT (v-akt murine thymoma viral oncogene homologs 1, 2, 3) (alias: PKB): AKT1 (14q32); AKT2 (19q13); AKT3 (1q44) (Altomare and Testa, 2007); - BAD (11q13) (BCL2-antagonist of cell death); - CASP9 (1p36) (caspase 9, apoptosis-related cysteine peptidase) (Bartolomeo and Cecconi, 2006); - CBL (11q23) (Cas-Br-M (murine) ecotropic retroviral transforming sequence) (Dikic and Schmidt, 2007); - CCND (cyclin D): CCND1 (11q13); CCND2 (12p13); CCND3 (6p21); - CDKN1A (6p21) (cyclin-dependent kinase inhibitor 1A) (Javelaud and Besancon, 2001); - CREBBP (16p13) (CREB binding protein (Rubinstein-Taybi syndrome)) (alias: CBP) (Kalkhoven, 2004); - ELK1 (Xp11) (ELK1, member of ETS oncogene family); - FOS (v-fos FBJ murine osteosarcoma viral oncogene homolog) and FOS-like antigen): FOS (14q24); FOSB (19q13); FOSL1 (11q13); FOSL2 (2p23) (Zenz, 2008); - FOXO (forkhead box O): FOXO1 (13q14); FOXO3 (6q21); FOXO4 (Xq13); FOXO6 (1p34) (Salih and Brunet, 2008); - FRAP1 (1p36) (alias mTOR) (Altomare and Testa, 2008); - FRS2 (12q15) (fibroblast growth factor receptor substrate 2) (Gotoh, 2008); - GAB1 (4q31) (GRB2-associated binding protein 1); - GRB2 (17q25) (growth factor receptor-bound protein 2) (Athauda and Bottaro, 2007); - INSR (19p13) (insulin receptor); - JAK (janus kinase (a protein tyrosine kinase)): JAK1 (1p31); JAK2 (9p24); JAK3 (19p13); TYK2 (19p13) (tyrosine kinase 2) (Murray, 2007; Shi and Amin, 2007; Steelman et al., 2008); - MAPK (mitogen-activated protein kinase ): MAPK1 (22q11) (alias: ERK2); MAPK3 (16p11) (alias: ERK1) (Seger and Krebs, 1995; Chang and Karin, 2001; Pearson et al., 2001); - MAP2K (mitogen-activated protein kinase kinase 1): MAP2K1 (15q22) (alias: MAPKK1, MEK1); MAP2K2 (19p13) (alias: MAPKK2, MEK2) (Seger and Krebs, 1995; Chang and Karin, 2001; Pearson et al., 2001); - MDM2 (12q15) (transformed mouse 3T3 cell double minute 2, p53 binding protein) (Duan and Villalona-Calero, 2006); - MYC (8q24) (v-myc myelocytomatosis viral oncogene homolog (avian)); - PDPK1 (16p13) (3-phosphoinositide dependent protein kinase-1) (alias: PDK1) (Dempsey et al., 2000); - PI3K (phosphoinositide-3-kinase, catalytic, alpha, beta, delta, gamma polypeptide): PIK3CA (3q26); PIK3CB (3q22); PIK3CD (1p36); PIK3CG (7q22); - PKD1 (14q11) (protein kinase D) (alias: PRKCM (mu)) (Wang et al., 2006); - PLCG: (phospholipase C, gamma 1, 2): PLCG1 (20q12), PLCG2 (16q24); - PRKC: protein kinase C family (alias PKC): PRKCA (alpha) (17q24) (alias: PKCA); PRKCB (beta) (16p12) (alias: PKCB); PRKCD (delta) (3p21), PRKCE (epsilon) (2p21); PRKCG (gamma) (19q13) (alias: PKCC, PKCG); PRKCH (eta) (14q23) (alias: PKCL, PRKCI); (iota) (3q26) (alias: PKCI); PRKCQ (theta) (10p15); PRKCZ (zeta) (1p36) (alias: PKC2) (Dempsey et al., 2000; Poole et al., 2004; Leitges, 2007; Malavez et al., 2008; Nelson et al., 2008); - PTEN (10q23) (phosphatase and tensin homolog deleted on chromosome ten) (Yin and Shen, 2008); - PTPN11 (12q24) (protein tyrosine phosphatase, non-receptor type, 11) (alias: SHP2) (Gadina et al., 1999; Tartaglia and Gelb, 2005); - RAF (v-raf murine sarcoma viral oncogene homolog): ARAF (Xp11); BRAF (7q34); RAF1 (3p25) (Domingo and Schwartz, 2004); - RAS (RAS viral oncogene homolog): HRAS (11p15) (Harvey); KRAS (12p12) (Kirsten); NRAS (1p13) (neuroblastoma) (Watzinger and Lion, 1999); - RHEB (7q36) (ras homolog enriched in brain) (Nobukini and Thomas, 2004); - RIN1 (11q13) (ras and rab interactor 1); - RPS6KA1 (1p36) (ribosomal protein S6 kinase, 90kDa, polypeptide 1) (Roux, 2008); - SHC1 (1q21) (SHC (src homology 2 domain containing) transforming protein 1); - SOS1 (2p21) (son of sevenless homolog 1); - SPRY (sprouty homolog (Drosophila)): SPRY1 (4q28); SPRY2 (13q31); SPRY4 (5q31) (Guy et al., 2003; Mason et al., 2006); - STAT (signal transducer and activator of transcription): STAT1 (2q32); STAT2 (12q13); STAT3 (17q21); STAT4 (2q32); STAT5a (17q11); STAT5b (17q11); STAT6 (12q13) (Schindler et al., 2007); - TSC1 (9q34) (tuberous Sclerosis 1) (Nobukini and Thomas, 2004); - TSC2 (16p13) (tuberous Sclerosis 2) (Nobukini and Thomas, 2004); - YWHAQ (2p25) (alias: 14-3-3); Note: IP3 (inositol 1,4,5-trisphosphate), DAG (diacylglycerol), PIP3 (Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), are not genes/proteins.



Recent studies showed that KAL1 (Xp22; Kallmann syndrome 1 sequence) acts as an FGFR1-specific modulator and coligand that physically interacts with the FGFR1-FGF-heparin sulfate proteoglycan complex and amplifies the resulting downstream signaling responses (Gonzalez-Martinez et al., 2004). Note: KAL1, like FGFR1, is involved in Kallmann syndrome (see below). Proteins which contain either a Src homology (SH2) domain, or a phosphotyrosine binding (PTB) domain can be phosphorylated/activated by the dimerized/activated receptor (herein FGFR1). FRS2, GRB2 and partners FRS2 (fibroblast growth factor receptor substrate 2) contains a PTB domain. Activation of the FGF-FGFR complex allows FRS2 to be phosphorylated, and then bind to GRB2 (growth factor receptor-bound protein 2) and PTPN11 (protein tyrosine phosphatase, non-receptor type, 11, alias SHP2). FGFRs (as well as other receptor tyrosine kinases), and also SHC1 (SHC (src homology 2 domain containing) transforming protein 1), PTPN11 and GAB1 (GRB2-associated binding protein 1) can bind GRB2 (Athauda and Bottaro, 2007). Phosphorylation of SHC1 and GAB1 induces binding to GRB2 and SOS1 (son of sevenless homolog 1) (Nelson et al., 2008) resulting in a multi-protein complex (Fig 3). GRB2 is constituvely associated with SOS. RAS/RAF/MAPK pathway GRB2-SOS stimulates the exchange of GTP to GDP on RAS (RAS viral oncogene homolog). RAS induces a phosphorylation cascade towards the nucleus, involving RAF (v-raf murine sarcoma viral oncogene homolog), MAP2K1 (mitogen-activated protein kinase kinase 1, alias MAPKK or MEK), MAPK (mitogen-activated protein kinase, alias ERK), ELK1 (ELK1, member of ETS oncogene family) and RPS6KA1 (ribosomal protein S6 kinase, 90kDa, polypeptide 1), towards cell cycle processes, differentiation, and homeostasis. PTPN11 positively regulates the RAS/RAF/MAPK pathway (Athauda and Bottaro, 2007). PRKC, a member of the PLC gamma pathway, phosphorylates a number of substrates, including MAP2K and YWHAQ (alias: 14-3-3) (Nelson et al., 2008). PKD1, another PLC gamma pathway member, upregulates the RAS/RAF/MAPK pathway by phosphorylating RIN1 (ras and rab interactor 1) and blocking its interaction with RAS. PI3K/AKT/mTOR pathway The complex FRS2-GRB2-GAB1 enables tyrosine phosphorylation of GAB1. GAB1, then, activates the PI3K/AKT/mTOR pathway, involving PI3K (phosphoinositide-3-kinase, catalytic, alpha, beta, delta, gamma polypeptide), PIP3 (Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3)), and AKT (v-akt murine thymoma viral oncogene homologs 1, 2, 3, alias: PKB). AKT has a great number of targets (Fig 4),

FRAP1 (alias mTOR) in particular. It has a role in glucose homeostasis, ribosomes and proteines syntheses, angiogenesis, stem cell maintenance, differentiation, survival, apoptosis, and cell cycle (Altomare and Testa, 2007). PLC gamma pathway PLCG induces the pathway involving DAG (diacylglycerol) and IP3 (inositol 1,4,5-trisphosphate) by lipid hydrolysis of PtdIns(4,5)P2, a rise of intracellular Ca++ concentration, PRKC (protein kinase C), and PKD1 (protein kinase D) through phosphorylation towards ion channels regulations, and various processes such as cell growth and differentiation, apoptosis and survival, cell motility and immune response. To be noted that PDPK1, regulated by PI3K from the PI3K/AKT/mTOR pathway, phosphorylates PRKC (Dempsey et al., 2000; Wang, 2006; Kheifets and Mochly-Rosen, 2007). JAK/STAT pathway PTPN11, once activated in the FRS2/PTPN11/GRB2/GAB1/SOS complex, provokes STAT (signal transducer and activator of transcription) dephosphorylation (review on JAK-STAT in Schindler et al., 2007). PRKC (member of the PLC gamma pathway) regulates STATs (Malavez et al., 2008). The JAK/STAT pathway regulates transcription, cell growth and differentiation, inflammation and immune response. IKK/NF-KB pathway PKD1 activates the NF-KB pathway. AKT, a member of the PI3K/AKT/mTOR pathway, activates CHUK (10q24, alias IKKA) (Altomare and Testa, 2007). RPS6KA1, a member of the RAS/RAF/MAPK pathway, inactivates NFKBIA (14q13) (Roux, 2008). PRKC regulates NFKB (Malavez et al., 2008). The IKK/NFKB pathway regulates survival processes. SPRY and CBL inhibition SPRY (sprouty homolog (Drosophila)) competes with PTPN11 and FRS2 for binding to the GRB2-SOS complex, and inhibits the RAS/RAF/MAPK pathway. On the other hand, SPRY prevents CBL-mediated ubiquitylation, endocytosis and degradation of FGFR (Guy et al., 2003; Mason et al., 2006; Dikic and Schmidt, 2007). Note: SPRY, like FGFR1, is involved in nonsyndromic cleft lip and palate (see below). Nuclear FGFR1 FGFs may: 1- be secreted (FGF 3-10, 16-23) out of the cell, bind on surface receptors (FGFRs) of other cells and activate signaling cascades as above described; 2- remain intra cellular (FGF 11-14); or 3- both (FGF1, FGF2). Intracytoplasmic FGFs can translocate to the nucleus and act as nuclear signaling molecules. All the same, FGFRs can be found inserted in the cytoplasmic membrane, but also in the cytosol, and in the nuclear compartment (Fig 5).



Fig 5. Intracellular FGF and FGFR. Adapted from Bryant and Stow, 2005 and Stachowiak et al., 2007. dotted lines: migration; solid lines activations. ARF6 (14q21) (ADP-ribosylation factor 6); DNM2 (19p13) (dynamin 2); KPNB1 (17q21) (karyopherin beta 1, alias importin beta); PRKCD (3p21) (protein kinase C, alias PKCD); RAB5 (a, b, c) (3p14, 12q13, 17q21) (RAB5, member RAS). FGFR1 (and also FGFR2 and 3 but not FGFR4) contains an atypical transmembrane domain (TM), with a probable beta-sheet conformation, instead of the more membrane-stable alpha-helical conformation of other single TM tyrosine kinase receptors (Myers et al., 2003). ARF6 (14q21; ADP-ribosylation factor 6) and DNM2 (19p13; dynamin 2) facilitate surface FGFR1 internalization, RAB5 (RAB5; member RAS) facilitates the trafic into the endosome. RPS6KA1 would also favor FGFR1 release from the membrane to the cytosol and also prior to nuclear import. KPNB1 (17q21; importin beta) would facilitate FGFR1 nuclear import. VHL (3p25; von Hippel-Lindau tumor suppressor) is recruited to FGFR1-containing endosomal vesicles and exhibits a functional relationship with RAB5A and DNM2 in FGFR1 internalization. In cooperation with CREBBP, Nuclear FGFR1 (nFGFR1) up-regulates gene transcription of FGF2, CCND1 (11q13; cyclin D1), JUN (1p32; jun oncogene), NEFL (8p21; neurofilament, light polypeptide), TH (11p15; tyrosine hydroxylase) (Groth and Lardelli, 2002; Bryant and Stow, 2005; Hsu et al., 2006; Stachowiak et al., 2007).

Homology With other FGFR, namely: FGFR2, FGFR3, and FGFR4. FGFRL1 (4p16; fibroblast growth factor receptor-like 1) is a related protein that lacks the intracytoplasmic tyrosine kinase domain (Kim et al., 2001). FGFRs are highly conserved through evolution.

Implicated in Epithelial-to-mesenchymal transition Note FGFR1 is expressed during the mesoderm induction in the embryo. FGFR1 drives the epithelial-to-mesenchymal transition (EMT) of primitive epiblast cells into mesoderm cells (Ciruna et al., 1997; Ciruna and Rossant, 2001). In an EMT, epithelial cells lose their polarity, increase their motility, and begin to express mesenchymal markers, such as VIM (10p13; vimentin), becoming mesenchymal-like. This process has also been linked to cancer progression, in which epithelial cells lose differentiation markers, such as CDH1 (E-cadherin), and acquire increased migratory capacity, leading to stromal invasion and metastasis (Thiery, 2002; Acevedo et al., 2007).



Angiogenesis Note FGF2 is an angiogenic factor, through interaction with FGFR1. Prostaglandin E2 stimulates FGF2/FGFR1 signaling (Finetti et al., 2008). FGF1 activation of FGFR1 signaling was found restricted to ligand activation of the FGFR1beta isoform. Transfection of endothelial cells with human cDNA encoding FGFR1beta induced cellular proliferation and formation of neovascular structures (Zhang et al., 2006).

Stem-cell myeloproliferative disorder Disease Stem-cell myeloproliferative disorder involving lymphoid (T- and B-cell) and myeloid lineages, called the 8p11 myeloproliferative syndrome (EMS) with variable presentations, e.g. a polycythaemia vera evolving towards an atypical myeloproliferative disorder, or a T-cell lymphoblastic lymphoma relapsing as an acute myeloblastic leukemia (AML) (Chaffanet et al., 1998; Reiter et al., 1998; Smedley et al., 1998; Xiao et al., 1998; Popovici et al., 1999; Guasch et al., 2000; Mugneret et al., 2000; Demiroglu et al., 2001; Fioretos et al., 2001; Sohal et al., 2001; Roy et al., 2002; Guasch et al., 2003; Grand et al., 2004; Vizmanos et al., 2004; Belloni et al., 2005; Walz et al., 2005; De Melo and Reid, 2006; Etienne et al., 2007; Hidalgo-Curtis et al., 2008; Mozziconacci et al., 2008; Park et al., 2008; Richebourg et al., 2008). The myeloproliferative syndrome transforms rapidly into a myelomonocytic leukemia. It has usually a poor outcome, since it is refractory to current chemotherapies, including imatinib. It involves FGFR1 on 8p11-12, and a variable partner (Fig 6 and 7).

Prognosis Very poor (median survival: 12 mths).

Cytogenetics The translocations are: t(6;8)(q27; p12) involving FGFR1OP (FGFR1 Oncogene Partner) t(7;8)(q34;p12) involving TRIM24 (transcriptional intermediary factor 1) t(8;9)(p12;q33) involving CEP110 (Centrosome protein 110) (review in Mozziconacci et al., 2008) t(8;11)(p12;p15) ins(12;8)(p11;p12p21) involving FGFR1OP2 (FGFR1 oncogene partner 2) t(8;12)(p12;q15) involving CPSF6 (cleavage and polyadenylation specific factor 6, 68kDa)

t(8;13)(p12;q12 ) involving ZMYM2 (zinc finger, MYM-type 2, alias ZNF198) t(8;17)(p12;q11) involving MYO18A (myosin XVIIIA) t(8;17)(p12;q25) t(8;19)(p12;q13.3) involving ERVK6 (endogenous retroviral sequence K, 6) t(8;22)(p12;q11) involving BCR (breakpoint cluster region) The translocation is the sole anomaly in half of the cases; additional anomalies are: duplication of one of the derivative chromosomes: 15% (strangely the der(partner) and the der(8) are equally found); 7/del(7q): 10%; +21: 10%; +8: 5%.

Hybrid/Mutated gene 5' partner - 3' FGFR1. All the hybrid genes involve fusion of the 5' partner to FGFR1 exon 9.

Abnormal protein Fusion transcripts encode large proteins containing the N-term of the translocation partner, and the tyrosine kinase domain of FGFR1 in the C-term.

Oncogenesis Constitutive activation of FGFR1, due to the presence of dimerization domains in the partner. However, some of the above mentioned partners do not seem to carry dimerization domains. Such hybrids partner-FGFR1, like CPSF6-FGFR1, may be functional in the cytosol or in the nucleus.

Anaplastic large cell lymphoma Oncogenesis FGFR1 copy number gain was observed in 3 of 15 anaplastic large cell lymphoma (ALCL) cases (Mao et al., 2003).

Breast cancer Note FGFs and FGFRs are expressed during ductal morphogenesis and their expression decreases throughout pregnancy and lactation. FGFR1 is mainly expressed during ductal morphogenesis. Additionally, expression of a dominant negative FGFR2 in the mammary gland during pregnancy has been shown to inhibit lobuloalveolar development. Inducible FGFR1 activation results in increased lateral budding of the mammary ductal epithelium, and induces alveolar hyperplasia and invasive lesions in the mouse (Welm et al., 2002). Inducible FGFR1 activation disrupt cell polarity, induce proliferation, and promotes cell survival. Inducible FGFR1 activation leads to dissociation of CDH1 from the cell membrane and expression of mesenchymal markers (Xian et al., 2005).



Fig 6. FGFR1 fusion protein.

Oncogenesis Amplification of 8p11.2-p12 is reported to be found in 10 to 15% of all breast cancers (Ugolini et al., 1999). Amplification of 8p11.2-p12 seems to comprise at least 4 different and independant amplicons. One of those contains WHSC1L1 (Wolf-Hirschhorn syndrome candidate 1-like 1), DDHD2 (DDHD domain containing 2), BLP1 (BBP-like protein 1; alias TM2D2), PPAPDC1B (phosphatidic acid phosphatase type 2 domain containing 1B), LSM1 (LSM1 homolog, U6 small nuclear RNA associated (S. cerevisiae)), and FGFR1. This 8p11-12 amplification has a pejorative effect on survival in breast cancer (Gelsi-Boyer et al., 2005). The FGFR1 region was found amplified in 9.4% of 319 breast tumors (Letessier et al., 2006). In an analysis of 33 primary breast tumors, FGFR1 was not included in the minimal region of amplification. Instead, the genes FLJ14299 (zinc finger protein 703; alias ZNF703), C8orf2 (ER lipid raft associated 2; alias ERLIN2), BRF2 (BRF2, subunit of RNA polymerase III transcription initiation factor, BRF1-like) and RAB11FIP1, mapped within the 8p11-12 minimal amplicon, and they showed a strong correlation between amplification and overexpression (Garcia et al., 2005). In 6 of 13 cases of classic lobular carcinomas, FGFR1's region was amplified and FGFR1 was tought to be the amplicon driver, since all cases with FGFR1 copy number gains also showed protein overexpression. Furthermore, siRNA directed against FGFR1 reduced cell viability of a breast cancer cell line (Reis-Filho et al., 2006). In a cohort of 880 breast tumours with various histology, FGFR1 amplification was observed in 8.7% of the tumours and was significantly more prevalent in patients over 50 years of age, and in tumours that lacked ERBB2/HER2 expression. FGFR1 amplification was confirmed as an independent prognostic factor for overall survival in patients with oestrogen-receptor-positive tumours, where FGFR1 amplification was the strongest independent predictor of a poor outcome (Elbauomy Elsheikh et al., 2007). FGFR1beta was found preponderant in breast cancer, and FGFR1alpha in normal breast cells (Luqmani et al., 1995). Finally, a S125L mutation was found in one of 25 cases of breast cancer (Stephens et al., 2005).

Prostate cancer Note The prostate is composed of stromal cells and epithelial cells. Stromal cells secrete paracrine factors for the maintenance and growth of the epithelium, some of which are under the control of androgens. FGF2, 7 and

9 are the main FGFs that the stromal cells secrete. Prostate epithelial cells express multiple FGF receptors. FGFR1 and FGFR2 are expressed in the basal epithelial cells of the prostate but not the luminal cells. FGFR3 IIIb and FGFR4 are also expressed in normal epithelium. FGFR1 is present exclusively as the IIIc isoform, while FGFR2 is present exclusively as the IIIb (FGF7 specific) isoform in the epithelium. FGFR3 is also present in prostatic epithelium, predominantly in the IIIb isoform. FGFR4 is also expressed in prostatic epithelium in the luminal epithelial cells (review in Kwabi-Addo et al., 2004).

Oncogenesis FGFR1 is over-expressed in benign prostatic hyperplasia whereas FGFR2-IIIc and FGFR3 are not (Boget et al., 2001). Transcripts for FGFR1 are found in prostate cancer cells (Shain et al., 2004), while FGFR2 is down regulated (Naimi et al., 2002). Both FGFR1 and FGFR4 have been found overexpressed in a study of 138 malignant prostates (Sahadevan et al., 2007). Chronic activation of FGFR1 in mouse prostate epithelial cells induces progressive prostate intraepithelial neoplasia (Wang et al., 2004). The FGFR1-IIIb isoform was expressed in all cases of prostate cancer, while FGFR1-IIIc mRNA was not. FGFR1-IIIb transcripts were detected in four out of six cases of benign prostatic hyperplasia (Leung et al., 1997). Although FGFR1 was found overexpressed in prostate cancer, it was without any significant correlation to clinical parameters including tumour grade, stage, and outcome, according to some studies (Leung et al., 1997; Giri et al., 1999). Conversely, Devilard et al., 2006 found that FGFR1, TACC1 (8p11; transforming, acidic coiled-coil containing protein 1) and WT1 (11p13; Wilms tumor 1) were expressed at higher level in prostate carcinoma samples than in benign prostate tissue, at both mRNA and protein levels, especially so in pT3 and N1/M1 samples. Transfection and expression of FGFR1 in premalignant cells accelerated progression to the malignant phenotype; restauration of FGFRIIIb in cells expressing FGFR1 restored epithelial cell differenciation (Feng et al., 1997). FGF2 was found in cells surrounding the cancer cells (fibroblasts and endothelium), and FGFR1 and FGFR2 expression were found increased in poorly differenciated prostate cancers, which would enhence the response of cancer cells to FGF2 (Giri et al., 1999). Activation of inducible FGFR1 led to epithelial-to-mesenchymal transition (like with breast cells) and progression to adenocarcinoma in the mouse. Mice not only developed well-differentiated adenocarcinoma,



but also exhibited several distinct malignant phenotypes: prostatic intraepithelial neoplasia, adenocarcinoma, transitional sarcomatoid-carcinoma, and frank sarcoma. Mice developed a greater incidence of a transitional sarcomatoid carcinoma with increasing age, consistent with the appearance of an epithelial-mesenchymal transition. Experimental up-regulation of FGFR1 provoked SOX9 increase. SOX9 (17q23; SRY (sex determining region Y)-box 9) is known to act with SNAI1 (20q13; snail homolog 1 (Drosophila)) and SNAI2 (8q12; snail homolog 2 (Drosophila)) to reduce CDH1, leading to a loss of cell-cell contact and increased migration (Acevedo et al., 2007). Enhanced mesenchymal expression of FGF10 leeds to the formation of cancers from murine prostate cells. Inhibition of FGFR1 signaling by dominant-negative FGFR1 reverts FGF10-induced adenocarcinoma (Memarzadeh et al., 2007). Amplification of FGFR1 and many other loci were found associated with the development of hormone resistance of the cancer cells (Edwards et al., 2003). SPRY1 (4q28; Sprouty1) and SPRY2 (13q31; Sprouty2) mRNAs, antagonists of FGF signaling (see above), are decreased in human prostate cancer (Kwabi-Addo, Wang et al., 2004; Fritzsche et al., 2006). Inducible FGFR1 provokes angiogenesis in the prostate of mice; ANGPT1 and ANGPT2 (angiopoietins 1 and 2, 8q23 and 8p23 respectively) were regulated by FGFR1 signaling and differentially expressed (Winter et al., 2007).

Bladder cancer Note FGFR1 is normally expressed in normal urothelium.

Oncogenesis Amplicons in 3p25 and 8p12 are frequent in bladder cancers. FGFR1 and RAF1 (3p25; v-raf-1 murine leukemia viral oncogene homolog 1) were found amplified in some bladder cancers and deleted in other (Simon et al., 2001).

Rhabdomyosarcoma (RMS) Note Muscle: FGFR1 blocks myogenesis by forcing the myoblasts to re-enter S-phase, instead of escaping in G1 to progress towards differenciation. Myoblast proliferation can be induced by a chimeric FGFR1 (Whitney et al., 2001). Myoblasts expressing a chimeric Fgfr1 were injected into infarcted hearts of mice. The treatment induced an increase in graft size, showing that selective proliferation can be induced (Stevens et al., 2007).

Oncogenesis FGFR1 over-expression was detected in 2 out of 2 embryonal rhabdomyosarcomas, 6 out of 6 alveolar rhabdomyosarcomas, and in the one pleomorphic adult variant tested, as well as in the RMS cell lines tested. A hypomethylation of a CpG island upstream to FGFR1

exon 1 was identified in the primary RMS tumors (Goldstein et al., 2007).

Glioblastoma Note FGFR1 is poorly expressed in normal glia. It is expressed as a form FGFR1alpha (containing the 3 Ig-like domains). Nuclear FGFR1 induces neuronal differentiation. FGFR1 is particularly expressed in the forebrain and in the midbrain-hindbrain boundary. FGFR1 may be the receptor for FGF8 mediated signaling in the midbrain-hindbrain boundary.

Oncogenesis In a study of 22 malignant astrocytomas, an alternatively spliced form FGFR1beta containing two Ig-like domains (and lacking Ig I, corresponding to exon 3, also called the alpha-exon) was preferentially expressed. Conversely, FGFR2 expression was abundant in normal white matter and in all low-grade astrocytomas but was not seen in malignant astrocytomas (Yamaguchi et al., 1994). FGFR1beta exhibits a tenfold higher affinity for FGF1 and FGF2 than FGFR1alpha. FGFR1 gene with alpha-exon inclusion targeted to glioblastoma cells had no discernable effect on cell growth in culture, but was associated with an increase in unstimulated CASP3 (4q35; caspase 3, apoptosis-related cysteine peptidase) and CASP7 (10q25; caspase 7, apoptosis-related cysteine peptidase) activity (Bruno et al., 2004). SFPQ (1p34; splicing factor proline/glutamine-rich, alias PTBP, polypyrimidine tract-binding protein) was identified as a regulator of FGFR1 splicing. SFPQ expression was found strongly increased in malignant glioblastoma multiforme tumors, but not in a low-grade astrocytoma case (Jin et al., 2000). Two mutations in FGFR1 were found (N546K and R576W), and no amplification, in a study of 19 glioblastomas (Rand et al., 2005).

Uveal melanoma Oncogenesis FGF1, FGF2 and FGFR1 are overexpressed in primary uveal melanomas. FGF2/FGFR1 mediate the RAS/RAF/MAPK over-activation which controls the proliferation of uveal melanoma cells (Lefevre et al., 2008).

Skin melanoma Oncogenesis Advanced stages of human melanoma have a high degree of vascularity. They express high levels of FGF2/FGFR1. Inhibiting FGF2 and FGFR1 suffices to inhibit tumor growth due to massive induction of melanoma cell apoptosis (Valesky et al., 2002).

Thyroid carcinoma Note FGFR2 is the only FGFR expressed in normal thyroid



tissue, and this expression is diminuished in thyroid cancer. FGFR1 is nearly not expressed in normal thyroid, but significantly expressed in multinodular goiter.

Oncogenesis Enhanced expression of FGF1, FGF2, and FGFR1 accompany thyroid hyperplasia and are not exclusively associated with the neoplastic state. These factors may be involved in the pathogenesis of uncontrolled thyroid growth observed in these conditions (Thompson et al., 1998). FGF2 immunoreactivity was detected in a small percentage and FGFR1 in a high percentage of adenomatous goiters (Shingu et al., 1998). FGFR1 is expressed in hyperplastic goiters, benign adenomas, and carcinomas (St Bernard et al., 2005). FGFR1 and FGFR3 are expressed in well-differentiated tumours, while FGFR4 is expressed in aggressive tumours. FGF2 and FGFR1 were both detected in a high percentage of papillary carcinomas, 10 follicular carcinomas, 3 anaplastic carcinomas (Shingu et al., 1998). FGFR1 is expressed in thyroid carcinoma cell lines through propagation of the MAPK activation and promotion of tumor progression. In contrast, FGFR2 is down-regulated. FGFR2-IIIb and FGFR1 compete with each other for FRS2 activation (Kondo et al., 2007).

Oral squamous cell carcinoma (OSCC) Oncogenesis An amplicon on 8p12 was found in a number of tumours. High FGFR1 expression was found in 12% of 178 tumours; there was a significant higher prevalence of T1/T2 versus T3/T4, stages I/II vs III/IV, but not between N0 and N1-3, nor in overall survival. Prevalence of low stages and superficial tumours may suggest a role of FGFR1 in the early steps of transformation of the oral epithelium (Freier et al., 2007).

Salivary gland tumors Note The expression of FGFR1 is highest early during gland development, inducing branching morphogenesis.

Oncogenesis In 10 patients with pleomorphic adenoma of the salivary gland, the expression of FGF1, FGF2, and FGFR1 appeared to be related to the proliferative activity of tumor cells in the tubular and solid areas, whereas loss of FGFR1 expression may be associated with the differentiation of tumor cells into myxoid and chondroid tissue types (Myoken et al., 1997). A subgroup of pleomorphic salivary gland adenomas showed a ring chromosome 8: r(8)(p12q12) with amplification of a hybrid gene 5'-FGFR1 3'-PLAG1, and also multiple copies of an intact PLAG1 (8q12; pleiomorphic adenoma gene 1) (Persson et al., 2008).

Esophageal squamous cell carcinoma Oncogenesis An amplicon on 8p12, including FGFR1, was found in 2 of 32 cases of esophagus cancer (Ishizuk et al., 2002). Co-expression of FGF1 and FGFR1 is predictive of a poor prognosis in patients with esophageal squamous cell carcinoma (Sugiura et al., 2007).

Hepatocellular carcinoma Note FGFR1 is exclusively expressed in nonparenchymal cells and FGFR4 exclusively expressed in the hepatocytes.

Oncogenesis Ectopic expression of FGFR1 in hepatocytes increased the number of proliferating hepatocytes but failed to induce preneoplasia or neoplasia. Ectopic FGFR1 was incapable of initiation of hepatomas; however, it was a strong promoter of carcinogenesis both as a proliferative enhancer and as a promoter of neoangiogenesis mediated by VEGF (6p12; vascular endothelial growth factor A) (Huang et al., 2006).

Colorectal carcinoma Oncogenesis FGFR1 is overexpressed, and FGFR3 is frequently downregulated in colorectal carcinoma. FGFR3 may promote cell differentiation (Jang 2005).

Lung cancer Oncogenesis Patients with high FGFR1 expression had significantly shorter survival than patients with weak or moderate expression. However, FGFR1 expression is not an independent prognostic factor in the presence of the stage (Volm et al., 1997). A single somatic mutation in FGFR1 (P252T) was observed in a bronchoalveolar cancer from a study of 26 primary lung neoplasms (Davies et al., 2005).

Pancreatic carcinoma Note At early stages of pancreas development, FGFR1-IIIb is expressed by pancreatic epithelial cells, while at later stages of development, FGFR1-IIIb expression decreases, concomitant with the expected decrease in the number of progenitor cells (Cras-Meneur and Scharfmann, 2002). FGF1alpha is expressed in normal pancreatic tissue.

Oncogenesis A significant correlation was found between FGFR1 expression level and advanced stages in pancreatic carcinoma. Low FGFR1 expression was correlated with longer survival (Ohta et al., 1995).



Patients with tumors that showed high expression of VEGF and FGF2 had significantly shorter survival (Kuwahara et al., 2003). Pancreatic adenocarcinoma overexpresses fibroblast growth factor ligands (FGF-1 and FGF-2) and FGFR1beta in about 90% of the time. Overexpression of FGFR1alpha inhibits pancreatic adenocarcinoma cells (Vickers et al., 2002). FGFR1-IIIc enhances and FGFR1-IIIb inhibits pancreatic cancer cell growth. Expression of FGFR1-IIIb inhibited the transformed phenotype of human pancreatic cancer cells. This was associated with a reduced p44/42 MAPK phosphorylation and an enhanced activity of JNK (10q11; JUN N-terminal kinase, alias MAPK8) and p38. The antiproliferative effects of FGFR1-IIIb were confirmed in a xenograft model. IIIc enhanced and IIIb inhibited basal cell proliferation in pancreatic cancer and non-cancer cells. Expression of FGFR1-IIIc in nonmalignant pancreatic ductal cells resulted in cellular transformation and in vivo tumor formation, whereas inhibition of FGFR1-IIIc resulted in a reversion of the malignant phenotype in pancreatic cancer cells. FGFR1-IIIc promotes pancreatic ductal adenocarcinomas cell growth through phosphorylation of FRS2, PLCG, and activation of the RAS/RAF/MAPK pathway (Kornmann et al., 2002; Liu et al., 2007). FGFR1-IIIb and FGFR1-IIIc are coexpressed in pancreatic cancer and these isoforms are differentially regulated by growth factors FGFs, IGF1R (15q26; insulin-like growth factor 1 receptor) and EGF (4q25; epidermal growth factor), and by CCND1 (11q13; cyclin D1) (Chen et al., 2008).

Pfeiffer syndrome Note Signaling in endochondral bone formation in the embryo: Null mice embryos lacking Fgfr1 die shortly after gastrulation. Prehypertrophic chondrocytes, hyperthrophic chondrocytes and osteoblasts express FGFR1. In mature bone, Fgfr1 and Fgfr2 continue to be expressed in osteoblasts (Ornitz, 2005; White et al., 2005). FGFR1 may function as a negative regulator of long bone development rather than increasing skull bone growth. FGFR1 expression is positively regulated by thyroid hormone T3 in osteoblasts. FGFR1 is important for early limb bud development and distal skeletal patterning. It is expressed in limb bud mesenchyme that gives rise to mesenchymal condensations and eventually to the chondrogenic and osteogenic lineage. Inactivation of FGFR1 in osteo-chondro-progenitor cells delayed osteoblast differentiation; conversely, inactivation of FGFR1 in differentiated osteoblasts accelerated differentiation. It appears that FGFR1 expression in osteoblasts is necessary to maintain the balance between bone formation and remodeling (Jacob et al., 2006). Pfeiffer syndrome is due to an activating mutation of FGFR1.

Disease Pfeiffer syndrome is an autosomal dominant

craniosynostosis syndrome. It is defined by the association of a coronal synostosis, with or without sagittal synostosis, turricephaly, hydrocephalus, hypertelorism, low nasal bridge, radiohumeral synostosis, broad thumbs and first toes, partial syndactyly, and usually no mental deficiency. Type I to III have been defined according to the severity of the symptoms (Webster and Donoghue, 1997; for review on craniosynostosis, see Cunningham et al., 2007). Pfeiffer syndrome is due to mutations in FGFR1 or in FGFR2. A unique mutation in FGFR1 is known to provoke Pfeiffer syndrome: P252R, where a proline is replaced by an arginine in the IgII-III linker region (see figure I) (Muenke et al., 1994; Schell et al., 1995; Rossi et al., 2003; Ibrahimi et al., 2004). Pfeiffer syndrome with a mutation in FGFR2 exhibits the heavier form, those with a mutation in FGFR1 exhibits the milder form (type I) of the disease. It is an activating mutation, which enhance the affinity of FGF9, causing inappropriate dimerization of FGFR1 and signal transduction (Ibrahimi et al., 2004). Note: Jackson-Weiss syndrome is caused by mutations in codons 342, 344, or 359, or deletion at codon 319 in FGFR2 gene. No case of Jackson-Weiss syndrome is due to a mutation in FGFR1, altough this is sometimes found written in databases.

Osteoglophonic/osteoglyphic dysplasia Note Activating mutations of FGFR1.

Disease Osteoglophonic dysplasia (or, better called, osteoglyphic dysplasia (Greenberg and Lewis, 1990)) is an autosomal dominant condition, but most cases are de novo. It is a skeletal dysplasia syndrome that shares characteristics with craniosynostosis syndromes and rhizomelic dwarfing syndromes. Features also include prominent supraorbital ridge, depressed nasal root, multiple unerupted teeth, diaphyseal fibrous lesions, and speech delay (Sklower Brooks et al., 1996). Mutations within FGFR1 are within the IgIII (also called D3) domain, the linker region and the initial transmembrane domain: N330I, Y374C, C381R (White et al., 2005; Farrow et al., 2006). They appear to be activating mutations, causing inappropriate dimerization of FGFR1.

Nonsyndromic cleft lip and palate (NS CLP) Note Loss-of-function mutations of FGFR1.

Disease Nonsyndromic cleft lip and palate (NS CLP) is a complex birth defect resulting from a combination of genetic and environmental factors, and the genetics of the disease are still poorly known. Mutations were found so far in MSX1 (4p16; msh homeobox 1), FOXE1 (9q22; forkhead box E1 (thyroid transcription



factor 2)), GLI2 (2q14; GLI-Kruppel family member GLI2), MSX2 (5q35; msh homeobox 2), SKI (1p36; v-ski sarcoma viral oncogene homolog (avian)), SPRY2 and, recently in FGF family members, namely: FGFR1, FGFR2, FGFR3, and FGF8. The mutations found in FGFR1 were I300T, M369I, E467K, and R609X. These loss-of-function mutations map to the IgIII-TM linker, the TM-TK linker, and to the TK domain. Penetrance appears to be incomplete (Kress et al., 2000; Riley et al., 2007).

Kallmann Syndrome (isolated idiopathic hypogonadotropic hypogonadism, isolated anosmia) Note Loss-of-function mutations of FGFR1.

Disease Kallmann syndrome (KS) is characterized by the association of anosmia and idiopathic or isolated hypogonadotropic hypogonadism (IHH) (pubertal development failure due to an impaired secretion of LH and FSH, in the absence of any hypothalamic-pituitary cause). Neurologic defects, including hearing loss, cleft palate, dental agenesis and renal aplasia may occur. Hypogonadism is due to gonadotropin releasing hormone (GnRH) deficiency and anosmia is related to hypoplasia of the olfactory bulbs; GnRH neurons originate in the nasal placode like olfactory neurons; they both migrate. GnRH neuroblasts formation/migration deficiency during embryogenesis may be responsible for Kallman syndrome (Gonzalez-Martinez et al., 2004). Incomplete penetrance of hypogonadism and/or anosmia is frequently described in Kallmann syndrome; cases may be inherited or sporadic. Kallmann syndrome is found in 10/100 000 males and 2/100 000 females. There is X-linked cases, autosomal dominant cases, and autosomal recessive transmissions. Kallmann syndrome is genetically heterogeneous, and may be due to mutations in KAL1 (Xp22.3; also called anosmin-1,causing the X-linked form of KS), FGFR1 (also called KAL2 for Kallmann 2, often associated with cleft palate and dental agenesis), PROK2 (3p13; prokineticin 2), and PROKR2 (20p12; prokineticin receptor 2). However, only 25% of Kallmann syndrome cases are due to mutations in these four genes. To be noted is that KAL1 has recently be found to acts as an FGFR1-specific modulator and coligand that physically interacts with the FGFR1-FGF-heparin sulfate proteoglycan complex (specifically through FGFR1 IIIc), and amplifies the FGF/FGFR1 downstream signaling responses in olfactory neuroblasts (Gonzalez-Martinez et al., 2004). Mutations or interstitial deletions in FGFR1 are found in 10% of individuals with Kallmann syndrome. Mutations within FGFR1 are variable: G48S, N77K, R78C, G97D, Y99C, 303-304insCC, C101F, V102I, S107X, D129A, A167S, C178S, D224H, G237S,

G237D, L245P, R250W (2 cases), R254Q, G270D, V273M (2 cases), E274G, C277Y, P283R, 936G->A, E324X, S332C, Y339C, A343V, S346C, c.1081G>C (splice site), R365fsX41, P366 liter, S439fs, A520T, I538V, V607M, Y613fsX42, K618fsX654, H621R, R622X, R622G, R622Q, 1970-1971delCA, c.1977+1G>A (splice site), R661X, W666R, Q680X, G687R, IV15+1G->A, G703S, G703R, M719R, P722S (2 cases), S685F, I693F, P722H and N724K double mutation, Y730X, P745S, P772S, V795I, R822C; However, the N77K and R822C changes were also found in healthy control individuals. The above noted mutations are dispersed in variable sites of FGFR1 (Ig domains, Ig-Ig linkers, IgIII-TM linker, TK domains, C-term); they appear to be dominant loss-of-function mutations. FGFR1 mutations also account for some of the mixed pedigrees, extending to hypogonadotropic hypogonadism and normal olfaction or, conversely, to isolated anosmia, or even asymptomatic carriers at times (Dode et al., 2003; Sato et al., 2004; Sato et al., 2005; Albuisson et al., 2005; Karges and de Roux, 2005; Pitteloud, Acierno et al., 2006; Pitteloud, Meysing, et al., 2006; Zenaty et al., 2006; Trarbach et al., 2008; Dode et al., 2007).

Depression, bipolar disorder, schizophrenia Disease Raised FGFR1 mRNA was found in the hippocampus and the gyrus in case of major depression and in cases with shizophrenia as well (Gaughan et al., 2006), and in the cortex of patients with major depression - but not in shizophrenia cases - (Tochigi et al., 2008). Conversely, decreased FGFR1 mRNA was found in the hippocampus in rats with social defeat experience (Turner, Calvo et al., 2008). Reduced density of dopamine neurons was found in transgenic mice expressing a dominant negative FGFR1 mutant; the mice presented similar structural and biochemical changes in dopamine neurons as what is found in shizophrenia patients (Klejbor et al., 2006). Caution must be taken when comparing the results, since, methodology, histology and anatomic regions of the cells under study, and diagnoses of the population studied may not be comparable from one study to another. Rats with an increased locomotor response to a novel environment exhibited increased FGFR1 mRNA in the hippocampus compared to other rats. Cocaine injections decreased FGFR1 mRNA in the hippocampus and increased FGFR1 mRNA in the prefrontal cortex. In rats with an increased locomotor response, cocaine decreased gene expression in the hippocampus and did not affect it in the prefrontal cortex, while, in other rats, cocaine did not affect gene expression in the hippocampus and increased gene expression in the prefrontal cortex (Turner, Flagel et al., 2008).



Breakpoints

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This article should be referenced as such:

Huret JL. FGFR1 (Fibroblast Growth Factor Receptor 1). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(11):821-840.

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