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Niche anchorage and signaling through membrane‐bound Kit‐ligand/c‐kit receptor are kinase independent and imatinib insensitive
Author(s) -
TaboneEglinger Séverine,
CalderinSollet Zuleika,
Pi Perrine,
Aebischer Nicole,
WehrleHaller Monique,
Jacquier MarieClaude,
Boettiger David,
WehrleHaller Bernhard
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-249425
Subject(s) - microbiology and biotechnology , tyrosine kinase , chemistry , biology , signal transduction
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.—Tabone‐Eglinger, S., Calderin‐Sollet, Z., Pinon, P., Aebischer, N., Wehrle‐Haller, M., Jacquier, M.‐C., Boettiger, D., Wehrle‐Haller, B., Niche anchorage and signaling through membrane‐bound Kit‐ligand/c‐kit receptor are kinase independent and imatinib insensitive. FASEB J. 28, 4441–4456 (2014). www.fasebj.org