The Extracellular Domain of Fibroblast Growth Factor Receptor 3 Inhibits Ligand-Independent Dimerization

Chen, Lirong; Placone, Jesse K.; Novicky, Lawrence; Hristova, Kalina

doi:10.1126/scisignal.2001195

Cited by 54 publications

(116 citation statements)

References 66 publications

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“…47 It has also been shown in another system, fibroblast growth factor receptor 3, that the ECD prevents ligand-independent receptor dimerization, thereby avoiding constitutive receptor signaling. 48 The ITC data presented herein for VEGFR-2 specify the distinct roles of individual extracellular subdomains in ligand-mediated dimerization; ECD subdomains 2 and 3 form the high-affinity ligand-binding site, whereas the energetically unfavorable homotypic interactions in domains 4-7 reduce the overall binding affinity. Tao et al showed previously that deletion of D4-7 led to constitutive ligand-independent receptor activation.…”

Section: Discussionmentioning

confidence: 76%

Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization

Brozzo

Bjelić

Kisko

et al. 2012

Blood

119

127

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VEGFs activate 3 receptor tyrosine kinases, VEGFR-1, VEGFR-2, and VEGFR-3, promoting angiogenic and lymphangiogenic signaling. The extracellular receptor domain (ECD) consists of 7 Ig-homology domains; domains 2 and 3 (D23) represent the ligandbinding domain, whereas the function of D4-7 is unclear. Ligand binding promotes receptor dimerization and instigates transmembrane signaling and receptor kinase activation. In the present study, isothermal titration calorimetry showed that the Gibbs free energy of VEGF-A, VEGF-C, or VEGF-E binding to D23 or the full-length ECD of VEGFR-2 is dominated by favorable entropic contribution with enthalpic penalty. The free energy of VEGF binding to the ECD is 1.0-1.7 kcal/mol less favorable than for binding to D23. A model of the VEGF-E/ VEGFR-2 ECD complex derived from smallangle scattering data provided evidence for homotypic interactions in D4-7. We also solved the crystal structures of complexes between VEGF-A or VEGF-E with D23, which revealed comparable binding surfaces and similar interactions between the ligands and the receptor, but showed variation in D23 twist angles. The energetically unfavorable homotypic interactions in D4-7 may be required for re-orientation of receptor monomers, and this mechanism might prevent ligand-independent activation of VEGFR-2 to evade the deleterious consequences for blood and lymph vessel homeostasis arising from inappropriate receptor activation. (Blood. 2012;119(7):1781-1788) IntroductionA plethora of growth factors, such as angiopoietins, VEGF family ligands, platelet-derived growth factors, fibroblast growth factors, and hepatocyte growth factors regulate blood and lymph vessel formation and homeostasis (reviewed in Cao 1 ). VEGFs represent a large family of ligands: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and PlGF, which bind to and activate in a combinatorial fashion 3 type V receptor tyrosine kinases (RTKs), VEGFR-1, VEGFR-2, and VEGFR-3, which give rise to highly specific signal output. In mammals, VEGF-A signaling through VEGFR-2 is the major angiogenic signaling pathway, but VEGF-C plays essential, and in some cases complementary, roles in the activation of this receptor (reviewed in Grünewald et al 2 ). The mechanism by which VEGFRs are activated is not understood in molecular detail, but clearly represents one of the many variations of RTK activation. In general, signaling by RTKs requires ligand-mediated dimerization with precise positioning of receptor subunits in active dimers. Dimeric ligand/receptor complexes subsequently initiate transmembrane signaling, resulting in the activation of the intracellular tyrosine kinase domains. 3,4 Active VEGFRs instigate cell signaling and promote endothelial cell migration and proliferation, as well as vessel fenestration and permeabilization. 5,6 The extracellular domain (ECD) of VEGFRs consists of 7 Ig-homology domains. The first 3 domains mediate ligand binding, 7,8 whereas the membrane proximal domains are involved in ligand-induced receptor dimerization. 7,9 Homotypic receptor i...

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Section: Discussionmentioning

confidence: 76%

Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization

Brozzo

Bjelić

Kisko

et al. 2012

Blood

119

127

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“…There have been previous attempts to use FRET to study FGFR dimerization in the context of plasma membrane (25,54,55). Because our approach utilizes non-cell-permeable fluorescent probes, it enabled a FRET-based approach to study FGFR interactions specifically on the cell surface in the context of physiological membrane environment and in the presence of intracellular scaffolding proteins that might affect FGFR dimerization.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, not only the ECD but also other parts of FGFR1 may have propensity to dimerize. Dimerization of isolated TMD in liposomes has been observed (24,25), and TKD could also contribute to receptor dimerization via interaction with intracellular signaling proteins (26,27). Indeed, very little is known about the cell surface dynamics of full-length FGFRs.…”

Section: Surfacementioning

confidence: 99%

“…Ligand-independent Dimerization-Previous studies suggested that each of the ECD, TMD, and TKD plays a role in ligand-independent dimerization via direct protein-protein interactions or indirect interactions with heparin or intracellular signaling proteins (25,26,47,48). We decided to test this notion using the TR-FRET system.…”

Section: Tmd and Tkd Play A Major Role In Fgfr1cmentioning

confidence: 99%

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Unliganded Fibroblast Growth Factor Receptor 1 Forms Density-independent Dimers

Comps-Agrar¹,

Dunshee²,

Eaton³

et al. 2015

Journal of Biological Chemistry

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Background:The nature of the FGFR1 signaling complex on the surface of living cells remains unclear. Results: A TR-FRET-based method revealed a ligand-independent dimer formation of FGFR1 that is independent of the cell-surface density. Conclusion: FGFR1 constitutively forms ligand-independent dimers that are either stabilized or undergo conformational changes in the presence of agonists. Significance: These findings help explain the mechanistic basis of FGFR1 activation by ligands and pathogenic mutations.

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“…The A206K mutation was introduced in eYFP to render it monomeric. The gene encoding EphA2 was subcloned between the HindIII and KpnI restriction sites in the pcDNA 3.1(ϩ) vector, which already contained a sequence encoding a 15-amino acid linker, followed by either mTurq or eYFP (30). Polymerase chain reaction (PCR) of the EPHA2 gene was performed using 5Ј-GGGC-CCAAGCTTACCAGCAACATGGAGCTCCAGGCAGCC-3Ј as a forward primer and 5Ј-CCCGGGGGTACCTTTGAT-GGGGATCCCCACAGTGTTCAC-3Ј as a reverse primer.…”

Section: Epha2mentioning

confidence: 99%

EphA2 Receptor Unliganded Dimers Suppress EphA2 Pro-tumorigenic Signaling

Singh

Ahmed

King

et al. 2015

Journal of Biological Chemistry

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Background:The EphA2 receptor tyrosine kinase can promote cell migration and cancer malignancy in the absence of ligand binding. Results:We uncover a correlation between unliganded dimerization and tumorigenic signaling. Conclusion: EphA2 pro-tumorigenic signaling is likely mediated by the EphA2 monomer. Significance: A therapeutic strategy that aims at the stabilization of EphA2 dimers may be beneficial for the treatment of cancers linked to EphA2 overexpression.

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The Extracellular Domain of Fibroblast Growth Factor Receptor 3 Inhibits Ligand-Independent Dimerization

Cited by 54 publications

References 66 publications

Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization

Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization

Unliganded Fibroblast Growth Factor Receptor 1 Forms Density-independent Dimers

EphA2 Receptor Unliganded Dimers Suppress EphA2 Pro-tumorigenic Signaling

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