ONCOGENIC MUTATION IN THE KIT RECEPTOR TYROSINE KINASE ALTERS SUBSTRATE-SPECIFICITY AND INDUCES DEGRADATION OF THE PROTEIN-TYROSINE-PHOSPHATASE SHP-1

Activating mutations in the Kit receptor tyrosine kinase have been ide ntified in both rodent and human mast cell leukemia, One activating Ki t mutation substitutes a valine for aspartic acid at codon 816 (D816V) and is frequently observed in human mastocytosis, Mutation at the equ ivalent position in the murine c-kit gene, involving a substitution of tyrosine for aspartic acid (D814Y), has been described in the mouse m astocytoma cell line P815. We have investigated the mechanism of oncog enic activation by this mutation, Expression of this mutant Kit recept or tyrosine kinase in a mast cell line led to the selective tyrosine p hosphorylation of a 130-kDa protein and the degradation, through the u biquitin-dependent proteolytic pathway, of a 65-kDa phosphoprotein, Th e 65-kDa protein was identified as the src homology domain 2 (SH2)-con taining protein tyrosine phosphatase SHP-1, a negative regulator of si gnaling by Kit and other hematopoietic receptors, and the protein prod uct of the murine motheaten locus. This mutation also altered the site s of receptor autophosphorylation and peptide substrate selectivity. T hus, this mutation activates the oncogenic potential of Kit by a novel mechanism involving an alteration in Kit substrate recognition and th e degradation of SHP-1, an attenuator of the Kit signaling pathway.