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- DOI: 10.1182/blood-2009-06-228460
- PMID: 20595514
- UKPMCID: 20595514
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I787 provides signals for c-Kit receptor internalization and functionality that control mast cell survival and development
Orinska, Zane; Föger, Niko; Huber, Michael; Marschall, Julia; Mirghomizadeh, Farhad; Du, Xin; Scheller, Marina; Rosenstiel, Philip; Goldmann, Torsten; Bollinger, Annalena; Beutler, Bruce A; Bulfone-Paus, Silvia
Blood. 2010;116(15):2665.
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Full-text held externally
- DOI: 10.1182/blood-2009-06-228460
- PMID: 20595514
- UKPMCID: 20595514
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.