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

Zane Orinska, Niko Föger, Michael Huber, Julia Marschall, Farhad Mirghomizadeh, Xin Du, Marina Scheller, Philip Rosenstiel, Torsten Goldmann, Annalena Bollinger, Bruce A. Beutler, Silvia Bulfone-Paus

Research output: Contribution to journalArticle

11 Scopus citations

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 Kit787F/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.

Original languageEnglish (US)
Pages (from-to)2665-2675
Number of pages11
JournalBlood
Volume116
Issue number15
DOIs
Publication statusPublished - Oct 14 2010

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

Cite this

Orinska, Z., Föger, N., Huber, M., Marschall, J., Mirghomizadeh, F., Du, X., ... Bulfone-Paus, S. (2010). I787 provides signals for c-Kit receptor internalization and functionality that control mast cell survival and development. Blood, 116(15), 2665-2675. https://doi.org/10.1182/blood-2009-06-228460