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

Authors:
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
Year of publication:
2010
Volume:
116
Issue:
15
Issn:
0006-4971
Journal title abbreviated:
BLOOD
Journal title long:
Blood
Impact factor:
11.841
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.