Two FGF Receptor Kinase Molecules Act in Concert to Recruit and Transphosphorylate Phospholipase Cγ

Huang, Zhifeng; Marsiglia, William M.; Roy, Upal; Rahimi, Nader; Ilghari, Dariush; Wang, Huiyan; Chen, Huaibin; Gai, Weiming; Blais, Steven P.; Neubert, Thomas A.; Mansukhani, Alka; Traaseth, Nathaniel J.; Li, Xiaokun; Mohammadi, Moosa

doi:10.1016/j.molcel.2015.11.010

Cited by 52 publications

(39 citation statements)

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“…PRE experiments were carried out on a selectively labeled 15 N tyrosine I707C mutant of FGFR2K conjugated with an MTSL spin label. MTSL labeling was carried out as previously described ( Huang et al, 2016 ). A 1 H/ 15 N HSQC spectrum was acquired for both the oxidized and reduced forms of the MTSL spin label.…”

Section: Materials and Methodsmentioning

confidence: 99%

Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases

Chen

Marsiglia

Cho

et al. 2017

eLife

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Receptor tyrosine kinase (RTK) signaling is tightly regulated by protein allostery within the intracellular tyrosine kinase domains. Yet the molecular determinants of allosteric connectivity in tyrosine kinase domain are incompletely understood. By means of structural (X-ray and NMR) and functional characterization of pathogenic gain-of-function mutations affecting the FGF receptor (FGFR) tyrosine kinase domain, we elucidated a long-distance allosteric network composed of four interconnected sites termed the ‘molecular brake’, ‘DFG latch’, ‘A-loop plug’, and ‘αC tether’. The first three sites repress the kinase from adopting an active conformation, whereas the αC tether promotes the active conformation. The skewed design of this four-site allosteric network imposes tight autoinhibition and accounts for the incomplete mimicry of the activated conformation by pathogenic mutations targeting a single site. Based on the structural similarity shared among RTKs, we propose that this allosteric model for FGFR kinases is applicable to other RTKs.DOI: http://dx.doi.org/10.7554/eLife.21137.001

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Section: Materials and Methodsmentioning

confidence: 99%

Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases

Chen

Marsiglia

Cho

et al. 2017

eLife

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“…[52] Therefore, DOCK studies were performed on an X-ray structure of nSH2 in complex with fibroblast growth factor receptor 2 (FGFR2; PDB ID: 5EG3). [53] As seen in and/or C-8 in compounds 6 and 7. Our previous study [7] reported that…”

Section: Docking Analyses For An Anticancer Effect Of Compound 10mentioning

confidence: 97%

“…The docked structure of compound 10 in complex with the X-ray structure coordinates of PLCγ1 (PDB ID: 5EG3). [53] (a) X-ray structure coordinates of a small FGFR2 peptide (PDB ID: 5EG3) and docked coordinates of 10 are both shown, and (b) only the docked coordinates of 10 are shown in the binding site of PLCγ1. P-TYR(769) in (a) is phosphorylated TYR residue of FGFR2, which phosphorylates nSH2 to activate PLCγ1 Similarly, brominated quinolines, 3,6,8-tribromoquinoline (5), TGI values between 20.4 and 52.7 μg/ml, except A549 cell line) have very strong antitumor effects against all tested cell lines (Table 1 and 2).…”

Section: Docking Analyses For An Anticancer Effect Of Compound 10mentioning

confidence: 99%

“…4.3.2 | Dock computations for the anticancer effect of compound 10 X-ray structure coordinates for phospholipase C gamma 1 (PLCγ1) in complex with fibroblast growth factor receptor 2 (FGFR2) were obtained from Protein Data Bank (PDB ID: 5EG3). [53] Molecular docking studies were performed using AutoDock_Vina v1.1.2. [66] Ligands and the receptor were prepared for docking by MGLTools v1.5.4, and the dock results were visualized by the same program.…”

Section: Molecular Docking For Enzyme Inhibitionmentioning

confidence: 99%

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Quinoline‐based promising anticancer and antibacterial agents, and some metabolic enzyme inhibitors

Ökten

Aydın

Koçyiğit

et al. 2020

Archiv der Pharmazie

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A series of substituted quinolines was screened for their antiproliferative, cytotoxic, antibacterial activities, DNA/protein binding affinity, and anticholinergic properties by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide cell proliferation, lactate dehydrogenase cytotoxicity, and microdilution assays, the Wolfe–Shimmer equality method, the Ellman method, and the esterase assay, respectively. The results of the cytotoxic and anticancer activities of the compounds displayed that 6‐bromotetrahydroquinoline (2), 6,8‐dibromotetrahydroquinoline (3), 8‐bromo‐6‐cyanoquinoline (10), 5‐bromo‐6,8‐dimethoxyquinoline (12), the novel N‐nitrated 6,8‐dimethoxyquinoline (13), and 5,7‐dibromo‐8‐hydroxyquinoline (17) showed a significant antiproliferative potency against the A549, HeLa, HT29, Hep3B, and MCF7 cancer cell lines (IC50 = 2–50 μg/ml) and low cytotoxicity (∼7–35%) as the controls, 5‐fluorouracil and cisplatin. The compound–DNA linkages are hyperchromic or hypochromic, causing variations in their spectra. This situation shows that they can be bound to DNA with the groove‐binding mode, with Kb value in the range of 2.0 × 103–2.2 × 105 M–1. Studies on human Gram(+) and Gram(−) pathogenic bacteria showed that the substituted quinolines exhibited selective antimicrobial activities with MIC values of 62.50–250 μg/ml. All tested quinoline derivatives were found to be effective inhibitors of acetylcholinesterase (AChE) and the human carbonic anhydrase I and II isoforms (hCA I and II), with Ki values of 46.04–956.82 nM for hCA I, 54.95–976.93 nM for hCA II, and 5.51–155.22 nM for AChE. As a result, the preliminary data showed that substituted quinolines displayed effective pharmacological features. Molecular docking studies were performed to investigate the binding modes and interaction energies for compounds 2–17 with AChE (PDB ID: 4EY6), hCA I (PDB ID: 1BMZ), and hCA II (PDB ID: 2ABE).

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“…FGFs activate transmembrane tyrosine kinases and their coupled intracellular signalling pathways to stimulate biological activities and transduce external signals through the PI3K, MAPK, and phospholipase Cg (PLCg) pathways (Klagsbrun, 1990;Zhou et al, 2009;Francavilla et al, 2013;Huang et al, 2016). A dual-receptor system comprising a family of four receptor tyrosine kinases (FGFRs) and heparan sulfate proteoglycans (HSPGs) mediates the stimulation of cellular metabolism by FGFs.…”

Section: Fgf Fgfmentioning

confidence: 99%

Progress in Research on the Role of FGF in the Formation and Treatment of Corneal Neovascularization

et al. 2020

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Corneal neovascularization (CNV) is a sight-threatening disease usually associated with inflammatory, infectious, degenerative, and traumatic disorders of the ocular surface. Fibroblast growth factor (FGF) family members play an important role in angiogenesis to induce corneal neovascularization, which significantly affects the differentiation, proliferation, metastasis, and chemotaxis of vascular endothelial cells. Both acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) demonstrate positive staining in capillaries and induce corneal stromal cells. The anabolism of endothelial cells is induced by bFGF in corneal neovascularization. FGFs exert their effects via specific binding to cell surface-expressed specific receptors. We believe that both anti-FGF antibodies and anti-FGF receptor antibodies represent new directions for the treatment of CNV. Similar to anti-vascular endothelial growth factor antibodies, subconjunctival injection and eye drops can be considered effective forms of drug delivery.

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Two FGF Receptor Kinase Molecules Act in Concert to Recruit and Transphosphorylate Phospholipase Cγ

Cited by 52 publications

References 40 publications

Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases

Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases

Quinoline‐based promising anticancer and antibacterial agents, and some metabolic enzyme inhibitors

Progress in Research on the Role of FGF in the Formation and Treatment of Corneal Neovascularization

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