BETA-2-INTEGRIN LFA-1 SIGNALING THROUGH PHOSPHOLIPASE C-GAMMA-1 ACTIVATION
BETA-2-INTEGRIN LFA-1 SIGNALING THROUGH PHOSPHOLIPASE C-GAMMA-1 ACTIVATION
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DOI：
10.1073/pnas.90.15.7099
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发表时间：
1993-08-01
影响因子：
11.1
通讯作者：
DAMLE, NK
中科院分区：
文献类型：
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作者：
KANNER, SB;GROSMAIRE, LS;DAMLE, NK
在造血细胞上发现的β 2-整联蛋白之一是淋巴细胞功能相关抗原1（LFA-1），这是一种淋巴细胞/骨髓细胞特异性受体，可与抗原呈递细胞上的细胞间粘附分子（ICAM）家族成员结合。用抗体或纯化的ICAM刺激LFA-1诱导T细胞抗原受体（TCR）-定向的T细胞应答性的增强。在本研究中，LFA-1被证明是连接到酪氨酸激酶信号通路，刺激酪氨酸磷酸化和激活磷脂酶C-γ 1（PLC-γ 1）。整合素β链（CD 18）交联独立诱导下游动员细胞内Ca 2+和有力的共刺激TCR诱导的Ca 2+流量的幅度和动力学的增加。通过该途径的β 2-整联蛋白信号传导被除莠霉素A完全抑制，并被TCR调节阻止。TCR通过抗体和LFA-1与可溶性ICAM-1/Rg融合蛋白形式的反受体的共连接导致PLC-γ 1的酪氨酸磷酸化延长。针对LFA-1的α链（CD 11 a）和β链（CD 18）的单克隆抗体诱导Ca 2+动员至不同水平，表明表位特异性活化潜力。除了PLC-γ 1，酪氨酸磷酸化的80 kDa的蛋白质底物增加后，CD 18交联，但不是TCR依赖性。因此，T细胞上的β 2-整联蛋白LFA-1与酪氨酸激酶途径直接相关，该途径刺激磷脂酰肌醇特异性PLC-γ 1的信号传导。
One of the beta2-integrins found on hematopoietic cells is lymphocyte function-associated antigen 1 (LFA-1), a lymphocyte/myeloid cell-specific receptor that binds to members of the intercellular adhesion molecule (ICAM) family on antigen-presenting cells. Stimulation of LFA-1 with antibodies or purified ICAMs induces augmentation of T-cell antigen receptor (TCR)-directed T-cell responsiveness. In the present study, LFA-1 was shown to be linked to the tyrosine kinase signaling pathway that stimulates tyrosine phosphorylation and activation of phospholipase C-gamma1 (PLC-gamma1). Integrin beta-chain (CD18) crosslinking independently induced down-stream mobilization of intracellular Ca2+ and potently costimulated TCR-induced Ca2+ flux with an increase in both amplitude and kinetics. Beta2-integrin signaling through this pathway was completely inhibited by herbimycin A and was prevented by TCR modulation. Coligation of the TCR via antibody and LFA-1 with a counter-receptor in the form of a soluble ICAM-1/Rg fusion protein resulted in prolonged tyrosine phosphorylation of PLC-gamma1. Monoclonal antibodies to both the alpha chain (CD11a) and the beta chain (CD18) of LFA-1 induced Ca2+ mobilization to different levels, suggesting epitope specificity for activation potential. In addition to PLC-gamma1, tyrosine phosphorylation of an 80-kDa protein substrate was augmented following CD18 crosslinking but was not TCR-dependent. The beta2-integrin LFA-1 on T cells is therefore directly linked to a tyrosine kinase pathway that stimulates signaling by phosphatidylinositol-specific PLC-gamma1.