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Niche anchorage and signaling through membrane-bound Kit-ligand/c-kit receptor are kinase independent and imatinib insensitive

Jacquier, Marie-Claude
Published in The FASEB journal. 2014, vol. 28, no. 10, p. 4441-4456
Abstract Kit ligand (KitL) and its tyrosine kinase receptor c-kit are critical for germ cells, melanocytes, mastocytes, and hematopoietic stem cells. Alternative splicing of KitL generates membrane-bound KitL (mb-KitL) or soluble KitL, providing survival or cell migration, respectively. Here we analyzed whether c-kit can function both as an adhesion and signaling receptor to mb-KitL presented by the environmental niche. At contacts between fibroblasts and MC/9 mast cells, mb-KitL, and c-kit formed ligand/receptor clusters that formed stable complexes, which resisted dissociation by c-kit blocking mAbs and provided cell anchorage under physiological shear stresses. Clusters recruited tyrosine-phosphorylated proteins and induced spatially restricted F-actin polymerization. Mutational analysis of c-kit demonstrated kinase-independent mb-KitL/c-kit clustering, anchorage, F-actin polymerization, and Tyr567-dependent cluster phosphorylation. Kinase inhibition of c-kit by imatinib reduced cluster coalescence, but allowed cluster phosphorylation and F-actin polymerization, which required PI3K recruitment and a newly identified juxtamembrane residue. Synergies between integrin and c-kit-mediated spreading and adhesion of MC/9 cells were studied in vitro on immobilized-KitL/fibronectin surfaces. While c-kit blocking antibodies prevented spreading, imatinib blocked spreading induced by soluble- but not immobilized KitL. Thus, "mechanical" activation of c-kit provides signaling, niche-anchorage, and synergies with integrin-mediated adhesion, which is independent of kinase function and resistant to c-kit kinase inhibitors.-
Keywords Actins/metabolismAnimalsBenzamides/pharmacologyCOS CellsCell AdhesionCell MovementCellular MicroenvironmentCercopithecus aethiopsFibroblasts/drug effects/metabolism/physiologyImatinib MesylateIntegrins/metabolismMast Cells/drug effects/metabolism/physiologyMicePhosphorylationPiperazines/pharmacologyProtein BindingProtein Kinase Inhibitors/pharmacologyProto-Oncogene Proteins c-kit/antagonists & inhibitors/genetics/metabolismPyrimidines/pharmacologySignal Transduction
PMID: 25002122
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Research group Migration cellulaire (645)
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TABONE-EGLINGER, Séverine et al. Niche anchorage and signaling through membrane-bound Kit-ligand/c-kit receptor are kinase independent and imatinib insensitive. In: The FASEB journal, 2014, vol. 28, n° 10, p. 4441-4456. doi: 10.1096/fj.14-249425 https://archive-ouverte.unige.ch/unige:89198

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Deposited on : 2016-11-21

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