Linked Life Data

15096041

Source:http://linkedlifedata.com/resource/pubmed/id/15096041

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
16
pubmed:dateCreated
2004-4-20
pubmed:abstractText
The current working model for fibroblast growth factor receptor (FGFR) dimerization and activation requires the assembly of a ternary complex of fibroblast growth factor (FGF), FGFR, and heparin or heparan sulfate proteoglycan (HSPG) on the plasma membrane. The recent FGF2-FGFR1-heparin crystal structure provides a detailed but static view of the FGF-FGFR-heparin complex. However, the kinetics of ternary complex assembly has yet to be investigated. Here, we characterize FGF2, FGFR1, and heparin interactions using surface plasmon resonance (SPR). Binding constants for binary FGF2/FGFR1 (KD = 62 nM), FGF2/heparin (KD = 39 nM), and FGFR1/heparin (KD = 3.2 microM) interactions correlate to the magnitude of binding interface observed in the FGF2-FGFR1-heparin crystal structure. Interestingly, comparison of sensorgrams of sequential injections of FGF2 and FGFR1 and equimolar FGF2-FGFR1 injections onto a heparin neoproteoglycan surface demonstrates that FGF2 dramatically enhances the association of FGFR1 with heparin and leads us to propose a model for the stepwise assembly of a ternary FGF-FGFR-HSPG complex. The weak binding affinity of the FGFR1-heparin interaction suggests that in this model, FGFR and HSPG are unbound in the absence of FGF ligand. The availability of FGF results in formation of initial FGF-HSPG complexes, which promotes the rapid binding of FGFR and creates a ternary complex capable of undergoing dimerization and subsequent FGFR activation. In contrast, alternative models for the kinetic assembly of a ternary complex in which binary FGF-FGFR or FGFR-HSPG complexes are intermediates do not conform well with the experimental data.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
27
pubmed:volume
43
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4724-30
pubmed:dateRevised
2010-5-26
pubmed:meshHeading
pubmed-meshheading:15096041-Dimerization, pubmed-meshheading:15096041-Fibroblast Growth Factor 2, pubmed-meshheading:15096041-Heparan Sulfate Proteoglycans, pubmed-meshheading:15096041-Heparin, pubmed-meshheading:15096041-Humans, pubmed-meshheading:15096041-Kinetics, pubmed-meshheading:15096041-Macromolecular Substances, pubmed-meshheading:15096041-Models, Chemical, pubmed-meshheading:15096041-Protein Processing, Post-Translational, pubmed-meshheading:15096041-Receptor, Fibroblast Growth Factor, Type 1, pubmed-meshheading:15096041-Receptor, Fibroblast Growth Factor, Type 2, pubmed-meshheading:15096041-Receptor Protein-Tyrosine Kinases, pubmed-meshheading:15096041-Receptors, Fibroblast Growth Factor, pubmed-meshheading:15096041-Signal Transduction, pubmed-meshheading:15096041-Surface Plasmon Resonance
pubmed:year
2004
pubmed:articleTitle
Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly.
pubmed:affiliation
Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.