Wiskott-Aldrich syndrome protein is an effector of Kit signaling
Wiskott-Aldrich syndrome protein is an effector of Kit signaling
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DOI：
10.1182/blood-2009-01-200733
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发表时间：
2009-10-01
期刊：
影响因子：
20.3
通讯作者：
Jahn, Thomas
中科院分区：
文献类型：
--
作者：
Mani, Maheswaran;Venkatasubrahmanyam, Shivkumar;Jahn, Thomas
多效性受体酪氨酸激酶试剂盒可以提供细胞骨架信号，定义细胞的形状，定位和迁移，但其潜在的机制还不太清楚。在这项研究中，我们提供的证据表明，试剂盒信号通过Wiskott-Aldrich综合征蛋白（WASP），中央造血肌动蛋白成核促进因子和调节细胞骨架。试剂盒配体（KL）刺激导致WASP以及相互作用蛋白WASP相互作用蛋白和Arp 2/3的瞬时酪氨酸磷酸化。KL诱导的骨髓源性肥大细胞（BMMCs）的丝状伪足在数量和大小上显着减少，在WASP的情况下。KL依赖性调节细胞内Ca 2+水平是异常的WASP缺陷的BMMC。当骨髓基质细胞来自WASP-杂合子雌性小鼠使用KL作为生长因子，文化最终开发的WASP阳性和阴性群体的混合物成一个同质的WASP阳性文化来自WASP阳性祖细胞。因此，WASP表达赋予了Kit依赖性造血发育的选择性优势，这与在WAS杂合女性人类中观察到的WASP阳性造血细胞的选择性优势一致。最后，KL介导的基因表达在野生型和WASP缺陷的BMMC进行了比较，并揭示了约30%的所有试剂盒诱导的变化是WASP依赖性的。结果表明，通过WASP的试剂盒信号是必要的正常试剂盒介导的丝状伪足形成，细胞存活和基因表达，并提供了新的见解的机制，其中WASP施加强大的选择性压力在造血。（血。2009; 114：2900-2908）
The pleiotropic receptor tyrosine kinase Kit can provide cytoskeletal signals that define cell shape, positioning, and migration, but the underlying mechanisms are less well understood. In this study, we provide evidence that Kit signals through Wiskott-Aldrich syndrome protein (WASP), the central hematopoietic actin nucleation-promoting factor and regulator of the cytoskeleton. Kit ligand (KL) stimulation resulted in transient tyrosine phosphorylation of WASP, as well as interacting proteins WASP-interacting protein and Arp2/3. KL-induced filopodia in bone marrow-derived mast cells (BMMCs) were significantly decreased in number and size in the absence of WASP. KL-dependent regulation of intracellular Ca2+ levels was aberrant in WASP-deficient BMMCs. When BMMCs were derived from WASP-heterozygous female mice using KL as a growth factor, the cultures eventually developed from a mixture of WASP-positive and -negative populations into a homogenous WASP-positive culture derived from the WASP-positive progenitors. Thus, WASP expression conferred a selective advantage to the development of Kit-dependent hematopoiesis consistent with the selective advantage of WASP-positive hematopoietic cells observed in WAS-heterozygous female humans. Finally, KL-mediated gene expression in wild-type and WASP-deficient BMMCs was compared and revealed that approximately 30% of all Kit-induced changes were WASP dependent. The results indicate that Kit signaling through WASP is necessary for normal Kit-mediated filopodia formation, cell survival, and gene expression, and provide new insight into the mechanism in which WASP exerts a strong selective pressure in hematopoiesis. (Blood. 2009; 114: 2900-2908)