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

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.

Pubmed ID: 20595514

Authors

  • Orinska Z
  • Föger N
  • Huber M
  • Marschall J
  • Mirghomizadeh F
  • Du X
  • Scheller M
  • Rosenstiel P
  • Goldmann T
  • Bollinger A
  • Beutler BA
  • Bulfone-Paus S

Journal

Blood

Publication Data

October 14, 2010

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • Cell Differentiation
  • Cell Line
  • Cell Survival
  • DNA Primers
  • In Vitro Techniques
  • Interleukin-3
  • Isoleucine
  • Mast Cells
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutagenesis, Site-Directed
  • Mutant Proteins
  • Point Mutation
  • Proto-Oncogene Proteins c-cbl
  • Proto-Oncogene Proteins c-kit
  • Signal Transduction
  • Stem Cell Factor