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

Item Type:Article
Title:I787 provides signals for c-Kit receptor internalization and functionality that control mast cell survival and development
Creators Name:Orinska, Z. and Foeger, N. and Huber, M. and Marschall, J. and Mirghomizadeh, F. and Du, X. and Scheller, M. and Rosenstiel, P. and Goldmann, T. and Bollinger, A. and Beutler, B.A. and Bulfone-Paus, S.
Abstract: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.
Keywords:Amino Acid Sequence, Amino Acid Substitution, Base Sequence, Cell Differentiation, Cell Line, Cell Survival, DNA Primers, Interleukin-3, Isoleucine, Mast Cells, Site-Directed Mutagenesis, Mutant Proteins, Point Mutation, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins c-kit, Signal Transduction, Stem Cell Factor, Animals, Mice
Publisher:American Society of Hematology
Page Range:2665-2675
Date:14 October 2010
Official Publication:https://doi.org/10.1182/blood-2009-06-228460
PubMed:View item in PubMed

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