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. 2019 May 14;8(5):455.
doi: 10.3390/cells8050455.

Cross-Talk Between Fibroblast Growth Factor Receptors and Other Cell Surface Proteins

Free PMC article

Cross-Talk Between Fibroblast Growth Factor Receptors and Other Cell Surface Proteins

Marta Latko et al. Cells. .
Free PMC article


Fibroblast growth factors (FGFs) and their receptors (FGFRs) constitute signaling circuits that transmit signals across the plasma membrane, regulating pivotal cellular processes like differentiation, migration, proliferation, and apoptosis. The malfunction of FGFs/FGFRs signaling axis is observed in numerous developmental and metabolic disorders, and in various tumors. The large diversity of FGFs/FGFRs functions is attributed to a great complexity in the regulation of FGFs/FGFRs-dependent signaling cascades. The function of FGFRs is modulated at several levels, including gene expression, alternative splicing, posttranslational modifications, and protein trafficking. One of the emerging ways to adjust FGFRs activity is through formation of complexes with other integral proteins of the cell membrane. These proteins may act as coreceptors, modulating binding of FGFs to FGFRs and defining specificity of elicited cellular response. FGFRs may interact with other cell surface receptors, like G-protein-coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs). The cross-talk between various receptors modulates the strength and specificity of intracellular signaling and cell fate. At the cell surface FGFRs can assemble into large complexes involving various cell adhesion molecules (CAMs). The interplay between FGFRs and CAMs affects cell-cell interaction and motility and is especially important for development of the central nervous system. This review summarizes current stage of knowledge about the regulation of FGFRs by the plasma membrane-embedded partner proteins and highlights the importance of FGFRs-containing membrane complexes in pathological conditions, including cancer.

Keywords: coreceptor; fibroblast growth factor receptors; membrane proteins; receptor cross-talk; signaling.

Conflict of interest statement

yeast two-hybrid


Figure 1
Figure 1
(a) Interplay between fibroblast growth factor receptors (FGFRs) and G-protein-coupled receptors (GPCRs) (a) and other receptor tyrosine kinases (RTKs) (b) in the regulation of downstream signaling. The extracellular region of FGFRs is composed of immunoglobulin like domains D1–D3 (gray) and the acidic box (AB; red). FGFRs are anchored in the plasma membrane by a single transmembrane helix (yellow). The cytosolic part of FGFRs consists of the juxtamembrane domain (JM) and the split tyrosine kinase domain (TK; black). GPCR–FGFR complexes may involve Src as a mediator between receptors or form functional heterocomplexes without involvement of Src. (b) FGFRs interact with other RTK members in the plasma membrane and can be directly activated by intracellular tyrosine kinase domains of partner proteins like Eph receptors or PDGFRs. EphA4 receptor contains the N-terminal ligand binding domain (LBD) followed by the cysteine rich domain (CDR) and two fibronectin type III domains (FN1–2). EphA4 is embedded in the membrane by a single transmembrane domain (TM). The cytosol-oriented region of EphA4 is composed of the tyrosine kinase domain (TK) and the sterile alpha motif (SAM). The TK domain of EphA4 interacts with JM region of FGFRs. PDGFRs contain five immunoglobulin-like domains (Ig1–Ig5) in their extracellular region, a single transmembrane span (TM), and intracellular juxtamembrane (JM) and tyrosine kinase (TK) domains. TK of PDGFRs directly phosphorylates FGFRs.
Figure 2
Figure 2
Cross-talk between FGFRs and various cell adhesion molecules. The interaction of particular FGFR with members of CAMs subgroup is indicated. The domain architecture of FGFR partner proteins is shown. Domains (where identified) responsible for the interaction between the partner protein and FGFR are indicated in red. (a) Cadherins reported to interact with FGFR1 and FGFR4 contain five EC domains in their extracellular region, a single transmembrane helix, and a cytosoilc tail interacting with several signaling proteins. (b) Nectins are composed of three immunoglobulin-like domains Ig1–Ig3, a single transmembrane domain, and a cytosolic region. Nectins bind FGFR1 using the Ig3 domain (c) Neuroplastin (Np55) contains two immunoglobulin-like Ig1–Ig2 domains in their extracellular region and are embedded in the membrane by a single transmembrane helix, exposing short tail into the cytosol. Np55-FGFR1 interaction involves the Ig2 domain of Np55 (d) NCAMs expose on the surface of the cells five immunoglobulin-like domains Ig1–Ig5 and two fibronectin type III domains FN1 and FN2. The cytosolic tail of NCAMs varies in length. NCAMs bind FGFR1-FGFR3 using FN1–FN2 domains (e) L1-CAM is a single spanning plasma membrane protein with six Ig-like domains (Ig1–Ig6) and five fibronectin type III domains (FN1–FN5) in its extracellular region. FGFR1 binding requires the FN1–FN5 region of L1-CAM (f) Neurexins contain different numbers of the laminin-neurexin-sex hormone binding globulin domains (LNS) and three EGF-like domains (EGFL1–3), a single transmembrane span and the cytosolic tail interacting with cytoskeletal and signaling proteins. The extracellular region of neurexin 1-β interacts with FGFR1. (g) Ig-LON family members: OPCML and NEGR1 interact with FGFR1 and FGFR2. Ig-LON proteins contain three immunoglobulin-like domains Ig1–Ig3 that are implicated in FGFR binding. (h) FLRTs are single spanning transmembrane proteins containing the leucine-rich repeat domain (LRR) and the FN3 domain in their extracellular region. FLRTs employ the FN3 domain for FGFR1 and FGFR2 binding. (i) Integrins are composed of different α and β subunits. Integrin αvβ3 forms complexes with FGFR1.
Figure 3
Figure 3
Involvement of coreceptors in the FGFRs signaling. (a) Heparan sulfate proteoglycans (HSPGs) provide polysaccharide chains that stabilize FGF-FGFR complexes and regulate availability of ligands. HSPGs are either integral membrane proteins (syndecans) or secreted glycoproteins (perlecans), which form ternary complexes with FGF-FGFR. (b) Klotho proteins α (KLA) and β (KLB) are necessary for FGF23 and FGF19/FGF21 signaling, respectively.

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