A loss-of-function mutation of c-kit results in depletion of mast cells and interstitial cells of Cajal, while its gain-of-function mutation results in their oncogenesis

Loss-of-function mutations of the c-kit receptor tyrosine kinase (KIT) resu lt in depletion of mast cells and interstitial cells of Cajal (ICCs). In co ntrast, gain-of-function mutations of KIT induce neoplasms of mast cells an d ICCs. In humans, the sites of mutations are different between mast cell n eoplasms and those of ICCs. The former were found in the juxtamembrane doma in between the transmembrane and tyrosine kinase domains, and the latter in the tyrosine kinase domain. Moreover, the mechanism of constitutive activa tion is different. Point mutations and/or deletions in the juxtamembrane do main induced the KIT dimerization, and the dimerized KIT was activated. A p oint mutation at the particular aspartic acid in the tyrosine kinase domain induced spontaneous activation without forming dimers. Mutations of the c- kit gene are a good model for understanding the relationship between mutati ons and diseases in both humans and mice. (C) 2001 Elsevier Science B.V. Al l rights reserved.