Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration
Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration
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DOI：
10.1073/pnas.1834348100
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发表时间：
2003-09-16
影响因子：
11.1
通讯作者：
Schlessinger, J
中科院分区：
文献类型：
--
作者：
Okigaki, M;Davis, C;Schlessinger, J
通过同源重组靶向Pyk 2基因，探索了蛋白酪氨酸激酶Pyk 2的生物学作用。Pyk 2-/-小鼠是可行的和可生育的，没有明显的发育或行为障碍。然而，Pyk 2-/-巨噬细胞的形态和行为受损。从突变小鼠中分离的巨噬细胞不能极化，不能进行膜皱褶，也不能响应趋化因子刺激而迁移。此外，Pyk 2-/-巨噬细胞的板状伪足的收缩活性受损，如通过测量板状伪足上的纤连蛋白包被的珠粒朝向核的向后运动所揭示的，所述向后运动与由光镊产生的固定力相反。一致地，巨噬细胞浸润到角叉菜胶诱导的炎症区域在Pyk 2-/-小鼠中被强烈抑制。此外，在Pyk 2-/-巨噬细胞中，趋化因子刺激肌醇（1，4，5）三磷酸生产和Ca 2+释放，以及整合素诱导的Rho和磷脂酰肌醇3激酶活化受到损害。这些实验揭示了Pyk 2在巨噬细胞中的细胞信号传导中的作用，巨噬细胞对细胞迁移和功能至关重要。
The biological role of the protein tyrosine kinase, Pyk2, was explored by targeting the Pyk2 gene by homologous recombination. Pyk2-/- mice are viable and fertile, without overt impairment in development or behavior. However, the morphology and behavior of Pyk2-/- macrophages were impaired. Macrophages isolated from mutant mice failed to become polarized, to undergo membrane ruffling, and to migrate in response to chemokine stimulation. Moreover, the contractile activity in the lamellipodia of Pyk2-/- macrophages was impaired, as revealed by measuring the rearward movement toward the nucleus of fibronectin-coated beads on the lamellipodia in opposition to an immobilizing force generated by optical tweezers. Consistently, the infiltration of macrophages into a carageenan-induced inflammatory region was strongly inhibited in Pyk2-/- mice. In addition, chemokine stimulation of inositol (1, 4, 5) triphosphate production and Ca2+ release, as well as integrin-induced activation of Rho and phosphatidyl inositol 3 kinase, were compromised in Pyk2-/- macrophages. These experiments reveal a role for Pyk2 in cell signaling in macrophages essential for cell migration and function.