Dimerization and activation of the kit receptor by monovalent and bivalent binding of the stem cell factor.

摘要: Abstract The protooncogene c-kit encodes a tyrosine kinase receptor for the stem cell factor (SCF). Mutants of were shown to confer pleiotropic defective phenotype and often display negative dominance in heterozygous mice. To explore involvement dimerization this genetic phenomenon, we employed both human ligand, which does not recognize murine receptor, rodent SCF, binds with 100-fold reduced affinity as compared SCF. SCF binding living cells was found induce rapid complete that involved activation catalytic function. Although can be attributed dimeric nature no dissociation Kit dimers occurred at high excess suggesting receptor-receptor interactions are also dimer stabilization. This supported by vitro formation heterodimers between proteins through monovalent species-specific By coexpression mouse fibroblasts, heterodimerization an increase rat accelerated rate down-regulation. When mutant lacking insert domain coexpressed wild-type observed significant decrease intact its coupling effector protein, namely phosphatidylinositol 3'-kinase. Our results favor model assumes initial step ligand binding, followed intermediate bound one arm molecule. predicts existence intrinsic site provides structural basis receptors.