Signal transduction by several KIT juxtamembrane domain mutations.
Mutations of KIT receptor tyrosine kinase are found in the majority of patients with mastocytosis and in most gastrointestinal stromal tumors. Oncogenic KIT mutations in GISTs are located in the KIT juxtamembrane domain (JMD), while codon 816 in the KIT kinase domain is mutated in systemic mastocytosis. We describe and characterize a mutation in the KIT-JMD named Kdelta27. We show that Kdelta27 mutant is constitutively dimerized and phosphorylated. Kdelta27 ectopic expression renders both the Ba/F3 cell line and primary cultures of bone marrow mast cells independent of cytokines for proliferation and cell survival. The classical signaling pathways activated by wild-type KIT upon ligand stimulation are constitutively activated by Kdelta27 and other JMD mutations. However, a side-to-side comparison revealed differences between the wild-type and JMD mutations. First, in vitro kinase assays reveal a change in peptide substrate specificity. Second, STAT proteins are preferentially phosphorylated by KIT mutants. Third, inhibitors of KIT kinase are more efficient on JMD mutations than on WT KIT. We conclude that Kdelta27 is a new oncogenic KIT mutation showing constitutive activation of downstream signaling pathways, and suggest that specific pathways are activated by oncogenic KIT.
Casteran
Nathalie
N
Molecular and Functional Hematopoiesis Laboratory, U119 INSERM, 27 Bd Leï Roure 13009 Marseille, France.
De Sepulveda
Paulo
P
Beslu
Nathalie
N
Aoubala
Mustapha
M
Letard
Sébastien
S
Lecocq
Eric
E
Rottapel
Robert
R
Dubreuil
Patrice
P
D000818:Animals; D002455:Cell Division / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D008024:Ligands; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000235:genetics*; D051381:Rats; D015398:Signal Transduction / Q000235:genetics*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
D018076:DNA, Complementary; D008024:Ligands; D019009:Proto-Oncogene Proteins c-kit