FGFR ligand binding and activation

Authored: de Bono, B, 2007-01-10 10:27:18 Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22 The FGFs are a family of 22 secreted glycoproteins that are sequestered in the extracellular matrix (ECM) through their interaction with heparin and heparin sulphate proteoglycans (HSPGs). Release of FGFs from the ECM through the action of heparinases or proteases allows FGFs to act in a paracrine or autocrine manner on local FGF receptors. Binding to the receptor is stabilized by cell surface HSPG, forming a ternary complex. A subset of FGFs (FGF19, 21 and 23) have lower affinity for heparin and HSPG and act in an endocrine manner over greater distances to regulate energy, bile acid, glucose, lipid phosphate, and vitamin D homeostasis. Binding of these ligands to their receptors is generally aided by the FGF-binding Klotho proteins. The intracrine subfamily of FGFs (FGF11, 12, 13 and 14) are not secreted but act intracellularly in an FGF receptor-independent manner to regulate electrical impulses in neurons.<br><br>There are four FGFR genes (FGFR1-4) encoding receptors with 3 extracellular immunoglobulin domains (D1-D3), a single pass transmembrane domain and an intracellular tyrosine kinase domain. D2 and D3 are necessary and sufficient for ligand binding, while D1 and a serine-rich region between D1 and D2 known as the acid box are thought to play a role in receptor autoinhibition. Exon skipping generates isoforms of FGF receptors lacking D1 and the acid box, and these receptors show higher affinity for ligand than their counterparts with 3 Ig domains. FGFR1, 2 and 3, but not FGFR4, are also subject to alternative splicing in the second half of the D3 domain to yield 'b' and 'c' isoforms, which are expressed predominantly in epithelial or mesenchymal tissue, respectively. FGF ligands are produced in either epithelial or mesenchymal tissue and bind to receptors of the opposite tissue type. An exception to this is FGF1 which can bind to both 'b' and 'c' isoforms. In general, the epithelial 'b' receptor isoforms bind a narrower range of ligands than the mesenchymal 'c' versions. <br><br>FGFRs also contain a short amino acid motif within the second immunoglobulin domain that shares sequence homology with functional motifs present in neural adhesion molecules such as NCAM and N-cadherin. This so called CAM homology domain (CHD) forms a contiguous sequence with the acid box region and is crucial for this mode of activation. Interactions between the neural cell adhesion molecules are important for a number of developmental events and have also been implicated in tumor progression. Although the interaction can be seen over most of the cell surface, it is not seen at points of cell-cell contact where the adhesion molecules accumulate at stable junctions. The FGFR interaction with N-cadherin and NCAM (but not FGF) is absolutely dependent on the presence of the acid box motif. As this motif can be spliced out of all four FGFRs, this suggests a mechanism that can regulate the interaction of the receptor with different ligand classes. Reviewed: Mohammadi, M, 2007-02-06 21:44:35

http://purl.obolibrary.org/obo/HINO_0016060

Authored: de Bono, B, 2007-01-10 10:27:18

Edited: de Bono, B, D'Eustachio, P, 2007-02-10 20:21:22

The FGFs are a family of 22 secreted glycoproteins that are sequestered in the extracellular matrix (ECM) through their interaction with heparin and heparin sulphate proteoglycans (HSPGs). Release of FGFs from the ECM through the action of heparinases or proteases allows FGFs to act in a paracrine or autocrine manner on local FGF receptors. Binding to the receptor is stabilized by cell surface HSPG, forming a ternary complex. A subset of FGFs (FGF19, 21 and 23) have lower affinity for heparin and HSPG and act in an endocrine manner over greater distances to regulate energy, bile acid, glucose, lipid phosphate, and vitamin D homeostasis. Binding of these ligands to their receptors is generally aided by the FGF-binding Klotho proteins. The intracrine subfamily of FGFs (FGF11, 12, 13 and 14) are not secreted but act intracellularly in an FGF receptor-independent manner to regulate electrical impulses in neurons.

There are four FGFR genes (FGFR1-4) encoding receptors with 3 extracellular immunoglobulin domains (D1-D3), a single pass transmembrane domain and an intracellular tyrosine kinase domain. D2 and D3 are necessary and sufficient for ligand binding, while D1 and a serine-rich region between D1 and D2 known as the acid box are thought to play a role in receptor autoinhibition. Exon skipping generates isoforms of FGF receptors lacking D1 and the acid box, and these receptors show higher affinity for ligand than their counterparts with 3 Ig domains. FGFR1, 2 and 3, but not FGFR4, are also subject to alternative splicing in the second half of the D3 domain to yield 'b' and 'c' isoforms, which are expressed predominantly in epithelial or mesenchymal tissue, respectively. FGF ligands are produced in either epithelial or mesenchymal tissue and bind to receptors of the opposite tissue type. An exception to this is FGF1 which can bind to both 'b' and 'c' isoforms. In general, the epithelial 'b' receptor isoforms bind a narrower range of ligands than the mesenchymal 'c' versions.

FGFRs also contain a short amino acid motif within the second immunoglobulin domain that shares sequence homology with functional motifs present in neural adhesion molecules such as NCAM and N-cadherin. This so called CAM homology domain (CHD) forms a contiguous sequence with the acid box region and is crucial for this mode of activation. Interactions between the neural cell adhesion molecules are important for a number of developmental events and have also been implicated in tumor progression. Although the interaction can be seen over most of the cell surface, it is not seen at points of cell-cell contact where the adhesion molecules accumulate at stable junctions. The FGFR interaction with N-cadherin and NCAM (but not FGF) is absolutely dependent on the presence of the acid box motif. As this motif can be spliced out of all four FGFRs, this suggests a mechanism that can regulate the interaction of the receptor with different ligand classes.

Reviewed: Mohammadi, M, 2007-02-06 21:44:35

Pubmed19247306

Pubmed8954625

Pubmed16597617

Pubmed20940169

Pubmed7730326

Reactome, http://www.reactome.org

Pubmed7730327

Pubmed20094046

FGFR ligand binding and activation

http://purl.obolibrary.org/obo/NCBITaxon_9606

HINO:0016060

FGFR ligand binding and activation

Reactome Database ID Release 43190376

GENE ONTOLOGYGO:0008543

ReactomeREACT_9396

http://purl.obolibrary.org/obo/INO_0000021

http://purl.obolibrary.org/obo/HINO_0016056

http://purl.obolibrary.org/obo/HINO_0016059

http://purl.obolibrary.org/obo/HINO_0016036

http://purl.obolibrary.org/obo/HINO_0016032

http://purl.obolibrary.org/obo/HINO_0016035