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

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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., Foeger, N., Huber, M., Marschall, J., Mirghomizadeh, F., Du, X., Scheller, M., Rosenstiel, P., Goldmann, T., Bollinger, A., 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
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	116
Number:	15
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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