Submitted February 26, 2007
Accepted June 22, 2007
The tyrosine kinase FES is an essential effector of KITD816V proliferation signal
Edwige Voisset, Sophie Lopez, Patrice Dubreuil, and Paulo De Sepulveda*
UMR599, Centre de Recherche en Cancerologie de Marseille, INSERM, Laboratoire d'Hematopoiese Moleculaire et Fonctionelle, Marseille, France
Institut Paoli-Calmettes, Marseille, France
Universite de la Mediterranee, Marseille, France
* Corresponding author; email: sepulveda{at}marseille.inserm.fr.
KIT is a tyrosine kinase receptor that is aberrantly activated in several neoplasms. In human pathologies, the most frequent mutation of KIT occurs at codon 816. The resulting KIT mutant protein is activated in the absence of ligand and is resistant to the clinically available inhibitors of KIT. In this report, we provide evidence for an essential function of the cytoplasmic tyrosine kinase FES downstream of KITD816V. FES is phosphorylated on tyrosine residues in cells that carry KITD816V mutation and this phosphorylation is KIT-dependent. Reduction of FES expression using RNA interference, results in decreased cell proliferation in human or murine cells harboring KITD816V, or the homologous mouse mutation KITD814Y. The reduced cell growth can be rescued using another cytokine (GM-CSF) and is not observed when the closely related FER gene is targeted. Finally, signaling downstream of KITD816V is altered in cells lacking FES expression. This study shows a major function of FES downstream of activated KIT receptor and thereby points to FES as a novel target in KIT-related pathologies.
