Vav1/2/3-null mice define an essential role for Vav family proteins in lymphocyte development and activation but a differential requirement in MAPK signaling in T and B cells.
Vav1/2/3-null mice define an essential role for Vav family proteins in lymphocyte development and activation but a differential requirement in MAPK signaling in T and B cells.
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DOI：
10.1084/jem.20030874
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发表时间：
2003-11-17
影响因子：
15.3
通讯作者：
Swat, W
中科院分区：
文献类型：
--
作者：
Fujikawa, K;Miletic, AV;Alt, FW;Faccio, R;Brown, T;Hoog, J;Fredericks, J;Nishi, S;Mildiner, S;Moores, SL;Brugge, J;Rosen, FS;Swat, W
Rho鸟嘌呤核苷酸交换因子的Vav家族被认为是协调淋巴细胞抗原受体下游的信号事件。迄今为止，三个高度相关的家族成员的表达模糊了Vav功能的阐明。我们培养了缺乏所有Vav家族蛋白的小鼠，并发现Vav缺失的小鼠不产生功能性T细胞或B细胞，完全不能产生T依赖性和T非依赖性的体液反应。而T细胞的发育在胸腺的早期阶段被阻断，未成熟的B系细胞在周围积聚，但在晚期“过渡”阶段停止。在机制上，我们发现Vav家族对于TCR和B细胞受体（BCR）诱导的Ca2+信号传导都是至关重要的，令人惊讶的是，它只需要在发育和成熟的T细胞中激活丝裂原活化蛋白激酶（MAPK），而不是在B细胞中激活。因此，在Vav-null小鼠中产生的大量未成熟B细胞可能是由于该谱系中完整的Ras/MAPK信号传导。虽然Vav1的单独表达对正常淋巴细胞发育是足够的，但我们的数据也揭示了Vav2和Vav3的谱系特异性作用，首次证明Vav3在T细胞中起关键的代偿功能。总之，我们确定了整个Vav蛋白家族在淋巴细胞发育和激活中的重要作用，并确定了该家族内部以及Vav与其他罗鸟嘌呤核苷酸交换因子之间功能冗余的限制。
The Vav family of Rho guanine nucleotide exchange factors is thought to orchestrate signaling events downstream of lymphocyte antigen receptors. Elucidation of Vav function has been obscured thus far by the expression of three highly related family members. We generated mice lacking all Vav family proteins and show that Vav-null mice produce no functional T or B cells and completely fail to mount both T-dependent and T-independent humoral responses. Whereas T cell development is blocked at an early stage in the thymus, immature B lineage cells accumulate in the periphery but arrest at a late “transitional” stage. Mechanistically, we show that the Vav family is crucial for both TCR and B cell receptor (BCR)–induced Ca2+ signaling and, surprisingly, is only required for mitogen-activated protein kinase (MAPK) activation in developing and mature T cells but not in B cells. Thus, the abundance of immature B cells generated in Vav-null mice may be due to intact Ras/MAPK signaling in this lineage. Although the expression of Vav1 alone is sufficient for normal lymphocyte development, our data also reveal lineage-specific roles for Vav2 and Vav3, with the first demonstration that Vav3 plays a critical compensatory function in T cells. Together, we define an essential role for the entire Vav protein family in lymphocyte development and activation and establish the limits of functional redundancy both within this family and between Vav and other Rho–guanine nucleotide exchange factors.
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影响因子：
30.5
作者：
Aifantis, I;Gounari, F;von Boehmer, H
通讯作者：
von Boehmer, H
影响因子：
11.4
作者：
Doody, GM;Billadeau, DD;Turner, M
通讯作者：
Turner, M
影响因子：
9.2
作者：
Holsinger, LJ;Graef, IA;Crabtree, GR
通讯作者：
Crabtree, GR
影响因子：
5.3
作者：
Moores, SL;Selfors, LM;Swat, W
通讯作者：
Swat, W
影响因子：
64.8
作者：
BUSTELO, XR;LEDBETTER, JA;BARBACID, M
通讯作者：
BARBACID, M