The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes.
The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes.
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DOI：
10.1084/jem.20111692
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发表时间：
2012-04-09
期刊：
影响因子：
--
通讯作者：
Zhou D
中科院分区：
文献类型：
--
作者：
Mou F;Praskova M;Xia F;Van Buren D;Hock H;Avruch J;Zhou D
在淋巴室缺乏Mst1和Mst2的小鼠中，胸腺细胞发育正常，但单阳性胸腺细胞表现出过度凋亡和胸腺出口大大减少，并伴有RhoA和Rac1趋化因子激活的丧失。Mst1激酶是小鼠T细胞粘附、迁移、增殖和凋亡的重要调节因子。在这项研究中，我们分析了造血细胞中缺乏Mst1和Mst2的小鼠。与野生型小鼠相比，这些双敲除（DKO）小鼠表现出循环和次级淋巴器官（slo）中成熟T细胞数量的严重减少。DKO小鼠的CD4+CD8 -和CD4 - CD8+单阳性（SP）胸腺细胞类似于野生型小鼠的成熟T细胞，但经历了过度的凋亡，它们从胸腺的出口量减少了约90%。即使直接放置在循环中，DKO SP胸腺细胞也不能进入slo。在SP胸腺细胞中，缺乏Mst1和Mst2可使鞘鞘醇-1磷酸和ccl21消失，诱导Mob1磷酸化、Rac1和RhoA GTP充电以及随后的细胞迁移。当被Mst1或Mst2磷酸化时，Mob1结合并激活胸腺中丰富的Rac1鸟苷核苷酸交换器Dock8。因此，Mst1和Mst2激酶控制着Rho GTPase的激活和SP胸腺细胞的迁移反应。
In mice lacking both Mst1 and Mst2 in the lymphoid compartment, thymocyte development is normal, but single-positive thymocytes exhibit excessive apoptosis and greatly diminished thymic egress, accompanied by loss of chemokine activation of RhoA and Rac1. The Mst1 kinase is an important regulator of murine T cell adhesion, migration, proliferation, and apoptosis. In this study, we analyze mice lacking both Mst1 and Mst2 in hematopoietic cells. Compared with wild-type mice, these double knockout (DKO) mice exhibit a severe reduction in the number of mature T cells in the circulation and in secondary lymphoid organs (SLOs). CD4+CD8− and CD4−CD8+ single-positive (SP) thymocytes in DKO mice resemble mature T cells of wild-type mice but undergo excessive apoptosis, and their egress from the thymus is reduced by >90%. Even when placed directly in the circulation, DKO SP thymocytes failed to enter SLOs. In SP thymocytes, deficiency of Mst1 and Mst2 abolished sphingosine-1 phosphate– and CCL21-induced Mob1 phosphorylation, Rac1 and RhoA GTP charging, and subsequent cell migration. When phosphorylated by Mst1 or Mst2, Mob1 binds and activates the Rac1 guanyl nucleotide exchanger Dock8, which is abundant in the thymus. Thus, the Mst1 and Mst2 kinases control Rho GTPase activation and the migratory responses of SP thymocytes.
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DOI：
10.1126/science.1170179
发表时间：
2009-04-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Nishikimi A;Fukuhara H;Su W;Hongu T;Takasuga S;Mihara H;Cao Q;Sanematsu F;Kanai M;Hasegawa H;Tanaka Y;Shibasaki M;Kanaho Y;Sasaki T;Frohman MA;Fukui Y
通讯作者：
Fukui Y
影响因子：
30.5
作者：
Katagiri, Koko;Imamura, Masashi;Kinashi, Tatsuo
通讯作者：
Kinashi, Tatsuo
影响因子：
5.4
作者：
Lei, Yu;Liu, Cunlan;Takahama, Yousuke
通讯作者：
Takahama, Yousuke
影响因子：
4.8
作者：
Bichsel, SJ;Tamaskovic, R;Hemmings, BA
通讯作者：
Hemmings, BA
影响因子：
64.8
作者：
Carlson, Corey M.;Endrizzi, Bart T.;Jameson, Stephen C.
通讯作者：
Jameson, Stephen C.