TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.
TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.
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DOI：
10.1126/scisignal.2000500
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发表时间：
2010-05-18
影响因子：
7.3
通讯作者：
Humphrey MB
中科院分区：
文献类型：
--
作者：
Peng Q;Malhotra S;Torchia JA;Kerr WG;Coggeshall KM;Humphrey MB
巨噬细胞和破骨细胞的活化和融合需要12 kD的衔接分子DNA激活蛋白（DAP 12），其含有基于免疫受体酪氨酸的活化基序（ITAM）。TREM 2（在髓样细胞上表达的触发受体-2）是破骨细胞中的主要DAP 12相关受体，并且与DAP 12缺乏类似，人类中TREM 2的缺失导致Nasu-Hakola病，其特征在于骨囊肿和痴呆。此外，体外实验表明，DAP 12或TREM 2的缺乏导致破骨细胞发育受损和单核破骨细胞的形成。在这里，我们证明了连接TREM 2激活磷脂酰肌醇3-激酶（PI 3 K），细胞外信号调节激酶1（ERK 1）和ERK 2，和鸟嘌呤核苷酸交换因子Vav 3;诱导细胞内钙（Ca 2+）的动员和肌动蛋白的重组;并防止细胞凋亡。信号传导衔接分子DAP 10在PI 3 K向信号传导复合物的TREM 2和DAP 12依赖性募集中发挥关键作用。含有Src同源2（SH 2）结构域的肌醇磷酸酶-1（SHIP 1）通过以SH 2结构域依赖性方式与DAP 12结合并阻止PI 3 K募集至DAP 12来抑制TREM 2和DAP 12诱导的信号传导。这些结果证明了SHIP 1与DAP 12的先前未表征的相互作用，其在功能上限制了TREM 2和DAP 12依赖性信号传导，并鉴定了SHIP 1通过直接阻断PI 3 K的结合和活化来调节关键的含ITAM受体的机制。
The activation and fusion of macrophages and of osteoclasts require the adaptor molecule DNAX-activating protein of 12 kD (DAP12), which contains immunoreceptor tyrosine-based activation motifs (ITAMs). TREM2 (triggering receptor expressed on myeloid cells–2) is the main DAP12-associated receptor in osteoclasts and, similar to DAP12 deficiency, loss of TREM2 in humans leads to Nasu-Hakola disease, which is characterized by bone cysts and dementia. Furthermore, in vitro experiments have shown that deficiency in DAP12 or TREM2 leads to impaired osteoclast development and the formation of mononuclear osteoclasts. Here, we demonstrate that the ligation of TREM2 activated phosphatidylinositol 3-kinase (PI3K), extracellular signal–regulated kinase 1 (ERK1) and ERK2, and the guanine nucleotide exchange factor Vav3; induced the mobilization of intracellular calcium (Ca2+) and the reorganization of actin; and prevented apoptosis. The signaling adaptor molecule DAP10 played a key role in the TREM2- and DAP12-dependent recruitment of PI3K to the signaling complex. Src homology 2 (SH2) domain–containing inositol phosphatase-1 (SHIP1) inhibited TREM2- and DAP12-induced signaling by binding to DAP12 in an SH2 domain–dependent manner and preventing the recruitment of PI3K to DAP12. These results demonstrate a previously uncharacterized interaction of SHIP1 with DAP12 that functionally limits TREM2- and DAP12-dependent signaling and identify a mechanism through which SHIP1 regulates key ITAM-containing receptors by directly blocking the binding and activation of PI3K.
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影响因子：
30.5
作者：
Hamerman, JA;Tchao, NK;Lanier, LL
通讯作者：
Lanier, LL
影响因子：
8.7
作者：
Lanier LL
通讯作者：
Lanier LL
影响因子：
20.3
作者：
Hazen, Amy L.;Smith, Michelle J.;Kerr, William G.
通讯作者：
Kerr, William G.
影响因子：
4
作者：
Faccio, R;Zou, W;Ross, FP
通讯作者：
Ross, FP
影响因子：
4.4
作者：
Hamerman, Jessica A.;Jarjoura, Vessica R.;Lanier, Lewis L.
通讯作者：
Lanier, Lewis L.