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I787 provides signals for c-Kit receptor internalization and functionality that control mast cell survival and development.

Blood | Oct 14, 2010

http://www.ncbi.nlm.nih.gov/pubmed/20595514

Mast cell (MC) differentiation, survival, and activation are controlled by the membrane tyrosine kinase c-Kit upon interaction with stem cell factor (SCF). Here we describe a single point mutation induced by N-ethyl-N-nitrosurea (ENU) mutagenesis in C57BL/6J mice-an A to T transversion at position 2388 (exon 17) of the c-Kit gene, resulting in the isoleucine 787 substitution by phenylalanine (787F), and analyze the consequences of this mutation for ligand binding, signaling, and MC development. The Kit(787F/787F) mice carrying the single amino acid exchange of c-Kit lacks both mucosal and connective tissue-type MCs. In bone marrow-derived mast cells (BMMCs), the 787F mutation does not affect SCF binding and c-Kit receptor shedding, but strongly impairs SCF-induced cytokine production, degranulation enhancement, and apoptosis rescue. Interestingly, c-Kit downstream signaling in 787F BMMCs is normally initiated (Erk1/2 and p38 activation as well as c-Kit autophosphorylation) but fails to be sustained thereafter. In addition, 787F c-Kit does not efficiently mediate Cbl activation, leading to the absence of subsequent receptor ubiquitination and impaired c-Kit internalization. Thus, I787 provides nonredundant signals for c-Kit internalization and functionality.

Pubmed ID: 20595514 RIS Download

Mesh terms: Amino Acid Sequence | Amino Acid Substitution | Animals | Base Sequence | Cell Differentiation | Cell Line | Cell Survival | DNA Primers | In Vitro Techniques | Interleukin-3 | Isoleucine | Mast Cells | Mice | Mice, Inbred C3H | Mice, Inbred C57BL | Mice, Mutant Strains | Mutagenesis, Site-Directed | Mutant Proteins | Point Mutation | Proto-Oncogene Proteins c-cbl | Proto-Oncogene Proteins c-kit | Signal Transduction | Stem Cell Factor