title: Anomalous inhibition of c-Met by the kinesin inhibitor aurintricarboxylic acid.
abstract: c-Met [the hepatocyte growth factor (HGF) receptor] is a receptor tyrosine kinase playing a role in various biological events. Overexpression of the receptor has been observed in a number of cancers, correlating with increased metastatic tendency and poor prognosis. Additionally, activating mutations in c-Met kinase domain have been reported in a subset of familial cancers causing resistance to treatment. Receptor trafficking, relying on the integrity of the microtubule network, plays an important role in activation of downstream targets and initiation of signalling events. Aurintricarboxylic acid (ATA) is a triphenylmethane derivative that has been reported to inhibit microtubule motor proteins kinesins. Additional reported properties of this inhibitor include inhibition of protein tyrosine phosphatases, nucleases and members of the Jak family. Here we demonstrate that ATA prevents HGF-induced c-Met phosphorylation, internalisation, subsequent receptor trafficking and degradation. In addition, ATA prevented HGF-induced downstream signalling which also affected cellular function, as assayed by collective cell migration of A549 cells. Surprisingly, the inhibitory effect of ATA on HGF-induced phosphorylation and signalling in vivo was associated with an increase in basal c-Met kinase activity in vitro. It is concluded that the inhibitory effects of ATA on c-Met in vivo is an allosteric effect mediated through the kinase domain of the receptor. As the currently tested adenosine triphosphate competitive tyrosine kinase inhibitors (TKIs) may lead to tumor resistance (McDermott U, et al., Cancer Res 2010;70:1625-34), our findings suggest that novel anti-c-Met therapies could be developed in the future for cancer treatment.
authors.affiliation: London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK.
authors.forename: Mina
authors.initials: M
authors.lastname: Milanovic
authors.forename: Simone
authors.initials: S
authors.lastname: Radtke
authors.forename: Nick
authors.initials: N
authors.lastname: Peel
authors.forename: Michael
authors.initials: M
authors.lastname: Howell
authors.forename: Virginie
authors.initials: V
authors.lastname: Carrière
authors.forename: Carine
authors.initials: C
authors.lastname: Joffre
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Kermorgant
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Parker
mesh_terms: D000494:Allosteric Regulation; D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001312:Aurintricarboxylic Acid; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D016547:Kinesins