Structural Basis for Selective Small Molecule Kinase Inhibition of Activated c-Met

Rickert, Keith; Patel, Sangita; Allison, Timothy J.; Byrne, Noel; Darke, Paul L.; Ford, Rachael E.; Guérin, David; Hall, Dawn L.; Kornienko, Maria; Lu, Jun; Munshi, Sanjeev; Reid, John C.; Shipman, Jennifer M.; Stanton, Elizabeth F.; Wilson, Kevin; Young, Jonathon R.; Soisson, S.M.; Lumb, Kevin J.

doi:10.1074/jbc.m110.204404

Cited by 35 publications

(38 citation statements)

References 30 publications

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“…Protection of αG is not due to the proposed concomitant change from the inactive to active MET kinase domain conformation. Rather, structures of the isolated kinase domain in active (PDB: 3Q6U) and inactive (PDB: 2WD1 and 2G15) monomeric states show that conformation of the αG-helix only subtly changes upon kinase activation in the absence of stable kinase dimerization (Rickert et al, 2011; Wang et al, 2006) (Fig. 6B).…”

Section: Resultsmentioning

confidence: 99%

Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

et al. 2017

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Summary The nuclear pore complex subunit TPR is found in at least five different oncogenic fusion kinases, including TPR-MET, yet how TPR fusions promote activation of kinases and their oncogenic activities remains poorly understood. Here we report the crystal structure of TPR(2-142), the MET fusion partner of oncogenic TPR-MET. TPR(2-142) contains a continuous 124-residue α-helix that forms an anti-parallel tetramer from two leucine zipper-containing parallel coiled coils. Remarkably, single mutations cause strikingly different conformations of the coiled coil, indicating its highly dynamic nature. We further show that fusion of TPR(2-142) to the MET intracellular domain strongly and selectively stabilizes the αG-helix of the MET kinase domain and mutations of only the TPR leucine zipper residues at the junction to MET, but not other leucine zipper residues, abolish kinase activation. Together, these results provide critical insight into the TPR structure and its ability to induce dimerization and activation of fusion kinases.

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Section: Resultsmentioning

confidence: 99%

Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

et al. 2017

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“…Among these, a class of events repeatedly covered by experiment is activation/self-processing/folding via intramolecular chaperoning as mediated by proteolysis (proforms of procaspase-7 [73], subtilisin [74][75][76], S-adenosylmethionine decarboxylase [77], L-aspartate -decarboxylase [78]). Another is functional activation/deactivation through phosphorylation, from the by-now textbook example of glycogen phosphorylases [79] to a number of proteins in information/signal transduction pathways (translation elongation factor eEF1A [80], Aurora-A kinase [81], receptor tyrosine kinase c-Met [82]). …”

Section: Accepted Manuscriptmentioning

confidence: 99%

In silico prediction and characterization of protein post-translational modifications

Gianazza

Parravicini

Primi

et al. 2016

Journal of Proteomics

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“…The extracellular domain provides binding site for HGF, the only ligand of c-Met [11]. The intracellular tyrosine kinase catalytic domain induces receptor activation via causing auto-phosphorylation of tyrosine on the receptor, including Tyr1234 and Tyr1235 which are docking sites for downstream signal transduction molecules [12]. There are also some serine/threonine residues on the intracellular domain and their phosphorylation plays role in regulating tyrosine kinase activity of the receptor.…”

Section: Introductionmentioning

confidence: 99%

PKG II reverses HGF-triggered cellular activities by phosphorylating serine 985 of c-Met in gastric cancer cells

Yao²,

Zhu

et al. 2016

Oncotarget

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Previous studies showed that type II cGMP-dependent protein kinase G (PKG II) could inhibit the activation of epidermal growth factor receptor (EGFR). Both c-Met and EGFR belong to family of receptor tyrosine kinases (RTKs) and have high molecular analogy. However, the effect of PKG II on c-Met activation is unclear. This study was designed to investigate the inhibitory effect of PKG II on the activation of c-Met and consequent biological activities. The results from CCK8 assay, Transwell assay and TUNEL assay showed that HGF enhanced cell proliferation and migration, and decreased cell apoptosis. Activated PKG II reversed the above changes caused by HGF. Immunoprecipitation and Western blotting results showed that PKG II could bind with c-Met and phosphorylate its Ser985, and thereby inhibited HGF-induced activation of c-Met and MAPK/ERK and PI3K/Akt/mTOR mediated signal transduction. When Ser985 of c-Met was mutated to Alanine for preventing phosphorylation of this site, the blocking effect of PKG II on c-Met activation was annulled. When Ser985 of c-Met was mutated to Aspartic acid for mimicking phosphorylation of this site, HGF-induced activation of c-Met was prevented. In conclusion, the results indicated that PKG II could block c-Met activation via phosphorylating Ser985 of this RTK.

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Structural Basis for Selective Small Molecule Kinase Inhibition of Activated c-Met

Abstract: The receptor tyrosine kinase c-Met is implicated in oncogen-

Cited by 35 publications

References 30 publications

Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

In silico prediction and characterization of protein post-translational modifications

PKG II reverses HGF-triggered cellular activities by phosphorylating serine 985 of c-Met in gastric cancer cells

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