A new tyrosine phosphorylation site in PLCγ1:: The role of tyrosine 775 in immune receptor signaling

被引:40
|
作者
Serrano, CJ [1 ]
Graham, L [1 ]
DeBell, K [1 ]
Rawat, R [1 ]
Veri, MC [1 ]
Bonvini, E [1 ]
Rellahan, BL [1 ]
Reischl, IG [1 ]
机构
[1] US FDA, Ctr Biol Evaluat & Res, Off Biotechnol Prod, Div Monoclonal Antibodies, Bethesda, MD 20014 USA
来源
JOURNAL OF IMMUNOLOGY | 2005年 / 174卷 / 10期
关键词
D O I
10.4049/jimmunol.174.10.6233
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Phospholipase C gamma (PLC gamma) is a ubiquitous gatekeeper of calcium mobilization and diacylglycerol-mediated events induced by the activation of Ag and growth factor receptors. The activity of PLC gamma is regulated through its controlled membrane translocation and tyrosine (Y) phosphorylation. Four activation-induced tyrosine phosphorylation sites have been previously described (Y472, Y771, Y783, and Y1254), but their specific roles in Ag receptor-induced PLC gamma 1 activation are not fully elucidated. Unexpectedly, we found that the phosphorylation of a PLC gamma 1 construct with all four sites mutated to phenylalanine was comparable with that observed with wild-type PLC gamma 1, suggesting the existence of an unidentified site(s). Sequence alignment with known phosphorylation sites in PLC gamma 2 indicated homology of PLC gamma 1 tyrosine residue 775 (Y775) with PLC gamma 2 Y753, a characterized phosphorylation site. Tyrosine 775 was characterized as a phosphorylation site using phospho-specific anti-Y775 antiserum, and by mutational analysis. Phosphorylation of Y775 did not depend on the other tyrosines, and point mutation of PLC gamma 1 Y775, or the previously described Y783, substantially reduced AgR-induced calcium, NF-AT, and AP-1 activation. Mutation of Y472, Y771, and Y1254 had no effect on overall PLC gamma 1 phosphorylation or activation. Although the concomitant mutation of Y775 and Y783 abolished downstream PLC gamma 1 signaling, these two tyrosines were sufficient to reconstitute the wild-type response in the absence of functional Y472, Y771, and Y1254. These,data establish Y775 as a critical phosphorylation site for PLC gamma 1 activation and confirm the functional importance of Y783.
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收藏
页码:6233 / 6237
页数:5
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