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J Allergy Clin Immunol. 2009 Nov;124(5):1088-98. doi: 10.1016/j.jaci.2009.08.038.

Mutation of tyrosine 145 of lymphocyte cytosolic protein 2 protects mice from anaphylaxis and arthritis.

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  • 1Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Abstract

BACKGROUND:

Lymphocyte cytosolic protein 2, also known as Src homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76), is an essential adaptor molecule in myeloid cells, where it regulates FcepsilonRI-induced mast cell (MC) and FcgammaR- and integrin-induced neutrophil (polymorphonuclear leukocyte [PMN]) functions. SLP-76 contains 3 N-terminal tyrosines at residues 112, 128, and 145 that together are critical for its function.

OBJECTIVE:

We sought to explore the relative importance of tyrosines 112, 128, and 145 of SLP-76 during MC and PMN activation.

METHODS:

We examined in vitro MC and PMN functions using cells isolated from knock-in mice harboring phenylalanine substitution mutations at tyrosines 112 and 128 (Y112/128F) or 145 (Y145F). We also examined the effects of these mutations on in vivo MC and PMN activation using models of anaphylaxis, dermal inflammation, and serum-induced arthritis.

RESULTS:

Mutations at Y112/Y128 and Y145 both interfered with SLP-76 activity; however, Y145F had a greater effect than Y112/128F on most in vitro FcR-induced functions. In vitro functional defects were recapitulated in vivo, where mice expressing Y145F exhibited greater attenuation of MC-dependent passive systemic anaphylaxis and PMN-mediated inflammatory responses. Notably, the Y145F mutation completely protected mice against development of joint-specific inflammation in the MC and PMN-dependent K/B x N model of arthritis.

CONCLUSION:

Our data indicate that Y145 is the most critical tyrosine supporting SLP-76 function in myeloid cells. Future efforts to dissect how Y145 mediates SLP-76-dependent signaling in MCs and PMNs will increase our understanding of these lineages and provide insights into the treatment of allergy and inflammation.

PMID:
19895996
[PubMed - indexed for MEDLINE]
PMCID:
PMC2778804
Free PMC Article
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