The c-kit receptor tyrosine kinase (KIT) is constitutively activated in three different types of neoplastic mast cell lines by naturally occurring mutations that result in substitutions of Val or Tyr for Asp in the phosphotransferase domain. In an effort to characterize the role of the Asp residue, we have investigated the properties of mutant KITs in which the Asp residue was deleted or mutated to a series of other amino acids. With the exception of rare instances, mutant KITs with substitutions of Asp were found to be constitutively phosphorylated on tyrosine and activated in the absence of the ligand, stem cell factor (SCF), whereas a deletion mutant lacking Asp (KIT) did not exhibit tyrosine phosphorylation and activation even after treatment with SCF. In addition to constitutive activation, furthermore, both highly activated substitution mutants (KIT and KIT) and modestly activated substitution mutants (KIT and KIT) were continuously degraded in the absence of SCF, whereas wild-type KIT (KIT) required SCF stimulation to undergo degradation. These results suggested that the Asp residue may play a crucial role in regulating enzymatic activity and expression of KIT and that various types of mutations at the Asp residue may generate oncogenic protein with constitutive activation and degradation.

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