Structural basis for fibroblast growth factor receptor activation

Moosa Mohammadi, Shaun K. Olsen, Omar A. Ibrahimi

Research output: Contribution to journalArticlepeer-review

581 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)107-137
Number of pages31
JournalCytokine and Growth Factor Reviews
Volume16
Issue number2 SPEC. ISS.
DOIs
StatePublished - Apr 2005
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • Endocrinology, Diabetes and Metabolism
  • Immunology and Allergy
  • Immunology

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