Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
FGFR1 splice variants - Isoforms
TABLE I : FGFs and targets FGFRs (from Zang et al., 2006)
FGFR 1c, 3c > 2c, 1b, 4Δ
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. 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.
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.
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).
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.
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).
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).
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).
Pfeiffer syndrome is due to an activating mutation of FGFR1.
FGFR1 (Fibroblast Growth Factor Receptor 1)
Atlas Genet Cytogenet Oncol Haematol. 2008-12-01
Online version: http://atlasgeneticsoncology.org/gene/113/fgfr1-(fibroblast-growth-factor-receptor-1)
2000-12-01 FGFR1 (Fibroblast Growth Factor Receptor 1) by Marie-Josèphe Pébusque
1998-03-01 FGFR1 (Fibroblast Growth Factor Receptor 1) by Jean-Loup Huret