Structural basis for fibroblast growth factor receptor activation

doi:10.1016/j.cytogfr.2005.01.008

Cytokine & Growth Factor Reviews

Volume 16, Issue 2, April 2005, Pages 107-137

https://doi.org/10.1016/j.cytogfr.2005.01.008 Get rights and content

Abstract

FGF signaling plays a ubiquitous role in human biology as a regulator of embryonic development, homeostasis and regenerative processes. In addition, aberrant FGF signaling leads to diverse human pathologies including skeletal, olfactory, and metabolic disorders as well as cancer. FGFs execute their pleiotropic biological actions by binding, dimerizing and activating cell surface FGF receptors (FGFRs). Proper regulation of FGF–FGFR binding specificity is essential for the regulation of FGF signaling and is achieved through primary sequence variations among the 18 FGFs and seven FGFRs. The severity of human skeletal syndromes arising from mutations that violate FGF–FGFR specificity is a testament to the importance of maintaining precision in FGF–FGFR specificity. The discovery that heparin/heparan sulfate (HS) proteoglycans are required for FGF signaling led to numerous models for FGFR dimerization and heralded one of the most controversial issues in FGF signaling. Recent crystallographic analyses have led to two fundamentally different models for FGFR dimerization. These models differ in both the stoichiometry and minimal length of heparin required for dimerization, the quaternary arrangement of FGF, FGFR and heparin in the dimer, and in the mechanism of 1:1 FGF–FGFR recognition and specificity. In this review, we provide an overview of recent structural and biochemical studies used to differentiate between the two crystallographic models. Interestingly, the structural and biophysical analyses of naturally occurring pathogenic FGFR mutations have provided the most compelling and unbiased evidences for the correct mechanisms for FGF–FGFR dimerization and binding specificity. The structural analyses of different FGF–FGFR complexes have also shed light on the intricate mechanisms determining FGF–FGFR binding specificity and promiscuity and also provide a plausible explanation for the molecular basis of a large number craniosynostosis mutations.

Section snippets

Identification and characterization of FGF ligands

The inception of the fibroblast growth factor (FGF) signaling field can be traced to year the 1939, when bovine brain extracts were shown to promote proliferation of fibroblast cell lines in vitro [1], [2]. Biochemical characterization of this mitogenic activity (termed FGF) from bovine pituitary and brain tissue [3], [4], showed that FGF activity was due to a ∼15 kDa molecule, which was termed basic FGF (bFGF) reflecting on its high isoelectric point [5], [6]. A second molecule with FGF

Models for FGFR dimerization

Ligand-induced receptor dimerization is a prerequisite for RTK activation. Receptor dimerization brings the cytoplasmic domains of the receptors in close vicinity of each other providing the opportunity for receptor trans autophosphorylation, subsequent tyrosine kinase activation and initiation of downstream signaling pathways [93]. Using a dominant negative approach initially applied to PDGFR and EGFR [94], [95], it was shown that FGFR dimerization is required for signal transduction [96], [97]

Analysis of pathogenic gain-of-function FGFR mutations provides insight into the mode of FGF–FGFR binding and dimerization

Gain-of-function missense mutations in FGFR1–3 are responsible for craniosynostosis [55], [137], [138], [139] and chondrodysplasia syndromes [56]. Craniosynostosis, the premature fusion of one or more cranial sutures, affects approximately 1 in 2500 individuals and is the clinical finding of over 100 distinct syndromes, including Apert syndrome (AS), Crouzon syndrome (CS), Muenke syndrome (MS), and Pfeiffer syndrome (PS). Chondrodysplasia syndromes, including achondroplasia and thanatophoric

Mutational studies confirm the physiological relevance of secondary ligand–receptor interface observed only in the symmetric “two-end” model

As described in Sections 2.3.1 Crystal structure of a 2:2 FGF2–FGFR1c symmetric dimer (PDB ID: 1CVS) reveals a heparin binding canyon; first crystallographic insight into the mechanism of FGFR dimerization, 2.3.2 Crystal structure of FGF2–FGFR1c–heparin ternary complex (PDB ID 1FQ9) reveals a symmetric “two-end” model for FGFR dimerization, dimerization in the symmetric “two-end” model is also promoted by secondary FGF–FGFR contacts. The secondary FGF–FGFR contact site in the symmetric

A canyon dimer also forms in the FGF1–FGFR2c–heparin crystal

In lieu of the incorrect conformation of linker proline in the asymmetric model, we analyzed the crystal packing in 1E0O to understand what other features of the asymmetric model may have been affected by the incorrect cis configuration of the invariant linker proline. Importantly, Blundell and coworkers also crystallized their FGF1–FGFR2c–heparin complex (PDB ID: 1E0O) under a high sulfate ion condition (1 M lithium sulfate), which we know facilitates canyon dimer formation. Indeed, examination

What is the stoichiometry of heparin in the FGF–FGFR dimerization?

The symmetric “two-end” model and asymmetric model differ with respect to both the stoichiometry and the minimal oligosaccharide length required to promote FGF–FGFR dimerization. In an effort to differentiate between these two models, Rosenberg and coworkers have recently studied the stoichiometry of the dimeric FGF–FGFR–HS complex using native gel analysis and concluded that the stoichiometry of the dimeric FGF1–FGFR1c–HS complex is 2:2:2 [155], as observed in the symmetric “two-end” model. In

A role for D1 and the D1–D2 linker region in receptor autoinhibition

A large body of structural and biochemical data show that D2, D3 and the interconnecting linker harbor all of the determinants for ligand binding and specificity. In addition, the recent crystal structure of the D1–D3 portion of FGFR3c in complex with FGF1, shows that D1 and the D1–D2 linker are completely disordered [131], providing solid structural evidence that these regions are dispensable for ligand binding. In contrast, the role of D1 and the D1–D2 linker, which contains a stretch of

The symmetric “two-end” model provides a molecular basis for HS specificity

The composition of HS in the periplasm has been shown to undergo major dynamic changes during development and recent data suggest that these spatial and temporal changes impact FGF signaling. Emerging data show that distinct HS motifs are required to promote binding and activation of different FGF–FGFR pairs. Interestingly, these data reveal that the HS requirements of different FGF–FGFR complexes do not simply reflect the sum of HS requirements of individual FGF and FGFR components, rather,

Epilogue

Receptor dimerization is a universal mechanism in RTK activation. The structural basis for receptor dimerization has been elucidated for several RTK subfamilies including EGFR, VEGF, TRK. These studies reveal that the mode of receptor dimerization varies greatly among RTK subfamilies and is likely tailored to meet their individual biological functions. The mechanism by which FGFs transduce their signal across cell membranes has been intensely studied over the past 30 years. Recent X-ray

Acknowledgements

We thank Jinghong Ma for help in figure preparation. This work was funded by NIH grant DE13686 to M.M.

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Structural basis for fibroblast growth factor receptor activation

Abstract

Section snippets

Identification and characterization of FGF ligands

Models for FGFR dimerization

Analysis of pathogenic gain-of-function FGFR mutations provides insight into the mode of FGF–FGFR binding and dimerization

Mutational studies confirm the physiological relevance of secondary ligand–receptor interface observed only in the symmetric “two-end” model

A canyon dimer also forms in the FGF1–FGFR2c–heparin crystal

What is the stoichiometry of heparin in the FGF–FGFR dimerization?

A role for D1 and the D1–D2 linker region in receptor autoinhibition

The symmetric “two-end” model provides a molecular basis for HS specificity

Epilogue

Acknowledgements

J Biol Chem

J Biol Chem

Cell

J Biol Chem

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

Mech Dev

J Biol Chem

Biochim Biophys Acta

Biochem Biophys Res Commun

Biochim Biophys Acta

Biochem Biophys Res Commun

Genomics

J Biol Chem

J Biol Chem

Am J Hum Genet

Cell

J Biol Chem

J Biol Chem

Bone

Eur Urol

J Biol Chem

J Biol Chem

Gene

J Biol Chem

Biochem Biophys Res Commun

Cell

Cell

Cell

J Biol Chem

Cell

J Exp Biol

Growth

Pituitary extracts and steroid hormones in the control of 3T3 cell growth

Proc Natl Acad Sci USA

Purification of a growth factor for ovarian cells from bovine pituitary glands

Proc Natl Acad Sci USA

An endothelial cell growth factor from bovine hypothalamus: identification and partial characterization

Proc Natl Acad Sci USA

Human endothelial cells: use of heparin in cloning and long-term serial cultivation

Science

Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor

Science

Heparin binds endothelial cell growth factor, the principal endothelial cell mitogen in bovine brain

Science

An angiogenic growth factor is expressed in human glioma cells

Embo J

Bovine fibroblast growth factor: comparison of brain and pituitary preparations

J Cell Biol

Structural evidence that endothelial cell growth factor beta is the precursor of both endothelial cell growth factor alpha and acidic fibroblast growth factor

Proc Natl Acad Sci USA

The heparin-binding (fibroblast) growth factor family of proteins

Annu Rev Biochem

Transforming gene from human stomach cancers and a noncancerous portion of stomach mucosa

Proc Natl Acad Sci USA

Isolation of a rearranged human transforming gene following transfection of Kaposi sarcoma DNA

Proc Natl Acad Sci USA

The human FGF-5 oncogene encodes a novel protein related to fibroblast growth factors

Mol Cell Biol

Characterization of the HST-related FGF.6 gene, a new member of the fibroblast growth factor gene family

Oncogene

Purification and characterization of a newly identified growth factor specific for epithelial cells

Proc Natl Acad Sci USA

Cloning and characterization of an androgen-induced growth factor essential for the androgen-dependent growth of mouse mammary carcinoma cells

Proc Natl Acad Sci USA