The tyrosine kinase FES is an essential effector of KITD816V proliferation signal.
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 KIT(D816V). FES is phosphorylated on tyrosine residues in cells that carry KIT(D816V) 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 KIT(D816V) or the homologous mouse mutation KIT(D814Y). The reduced cell growth can be rescued using another cytokine (granulocyte-macrophage colony-stimulating factor [GM-CSF]) and is not observed when the closely related fer gene is targeted. Finally, signaling downstream of KIT(D816V) 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.
Voisset
Edwige
E
Institut National de la Santé et de la Rècherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 599, Centre de Recherche en Cancérologie de Marseille, Laboratoire d'Hématopoïèse Moléculaire et Fonctionnelle, Marseille, France.
Lopez
Sophie
S
Dubreuil
Patrice
P
De Sepulveda
Paulo
P
D000818:Animals; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D016193:G1 Phase; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051578:Proto-Oncogene Proteins c-fes / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D016196:S Phase; D050791:STAT Transcription Factors / Q000145:classification / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D050791:STAT Transcription Factors; C052602:proto-oncogene protein c-fes-fps; D001224:Aspartic Acid; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; C496645:FES protein, human; D051578:Proto-Oncogene Proteins c-fes; D038762:Ribosomal Protein S6 Kinases, 70-kDa