Structural requirements of SLP-76 in signaling via the high-affinity immunoglobulin E receptor (FcεRI) in mast cells

Alexander Kettner, Vadim I Pivniouk, Lalit Kumar, Hervé Falet, Jeng Shin Lee, Richard Mulligan, Raif S. Geha

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

The adapter SLP-76 plays an essential role in FcεRI signaling, since SLP-76-/- bone marrow-derived mast cells (BMMC) fail to degranulate and release interleukin-6 (IL-6) following FcεRI ligation. To define the role of SLP-76 domains and motifs in FcεRI signaling, SLP-76-/- BMMC were retrovirally transduced with SLP-76 and SLP-76 mutants. The SLP-76 N-terminal and Gads binding domains, but not the SH2 domain, were critical for FcεRI degranulation and IL-6 secretion, whereas all three domains are essential for T-cell proliferation following T-cell receptor (TCR) ligation. Unexpectedly, the three tyrosine residues in SLP-76 critical for TCR signaling, Y112, Y128, and Y145, were not essential for IL-6 secretion, but were required for degranulation and mitogen-activated protein kinase activation. Furthermore, a Y112/128F SLP-76 mutant, but not a Y145F mutant, strongly reconstituted mast cell degranulation, suggesting a critical role for Y145 in FcεRI-mediated exocytosis. These results point to important differences in the function of SLP-76 between T cells and mast cells.

Original languageEnglish (US)
Pages (from-to)2395-2406
Number of pages12
JournalMolecular and Cellular Biology
Volume23
Issue number7
DOIs
StatePublished - Apr 2003
Externally publishedYes

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IgE Receptors
Mast Cells
Interleukin-6
T-Cell Antigen Receptor
Ligation
Bone Marrow
T-Lymphocytes
Cell Degranulation
src Homology Domains
Exocytosis
Mitogen-Activated Protein Kinases
Tyrosine
Cell Proliferation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Structural requirements of SLP-76 in signaling via the high-affinity immunoglobulin E receptor (FcεRI) in mast cells. / Kettner, Alexander; Pivniouk, Vadim I; Kumar, Lalit; Falet, Hervé; Lee, Jeng Shin; Mulligan, Richard; Geha, Raif S.

In: Molecular and Cellular Biology, Vol. 23, No. 7, 04.2003, p. 2395-2406.

Research output: Contribution to journalArticle

Kettner, Alexander ; Pivniouk, Vadim I ; Kumar, Lalit ; Falet, Hervé ; Lee, Jeng Shin ; Mulligan, Richard ; Geha, Raif S. / Structural requirements of SLP-76 in signaling via the high-affinity immunoglobulin E receptor (FcεRI) in mast cells. In: Molecular and Cellular Biology. 2003 ; Vol. 23, No. 7. pp. 2395-2406.
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