Mechanisms of constitutive activation of c-kit receptor tyrosine kinase.

We investigated the mechanism of constitutive activation of c-kit receptor tyrosine kinase (KIT) found in the FMA3 murine mastocytoma cell line, and compared it with the mechanisms observed in other tumor mast cell lines (the HMC-1 human mast cell leukemia cell line, the RBL-2H3 rat mast cell leukemia cell line, and the P-815 murine mastocytoma cell line). The c-kit gene obtained from FMA3 cells was found to have 21-base deletion at the juxtamembrane domain of KIT, thereby leading to the constitutive activation of KIT. The deletion at the juxtamembrane domain resulted in constitutive dimerization of c-kit proteins, whereas the point mutation that were detected at the kinase domain of KIT in HMC-1, RBL-2H3, and P-815 cells caused constitutive activation of KIT without dimerization. These constitutively activating mutations of c-kit may play a role in development of mast cell tumors.