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Blood. 2010 Oct 14;116(15):2665-75. doi: 10.1182/blood-2009-06-228460. Epub 2010 Jul 1.

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

Author information

1
Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany. zorinska@fz-borstel.de

Erratum in

  • Blood. 2011 Jun 30;117(26):7186.

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.

PMID:
20595514
DOI:
10.1182/blood-2009-06-228460
[Indexed for MEDLINE]
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