Activation of ErbB2 receptor tyrosine kinase supports invasion of endothelial cells by Neisseria meningitidis.
Activation of ErbB2 receptor tyrosine kinase supports invasion of endothelial cells by Neisseria meningitidis.
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DOI：
10.1083/jcb.200106148
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发表时间：
2001-10-01
期刊：
影响因子：
--
通讯作者：
Bourdoulous S
中科院分区：
文献类型：
--
作者：
Hoffmann I;Eugène E;Nassif X;Couraud PO;Bourdoulous S
ErbB2 是一种受体酪氨酸激酶，属于表皮生长因子 (EGF) 受体家族，通常参与细胞分化、增殖和肿瘤生长，并通过与家族其他成员的异二聚化来激活。我们在此表明，IV 型菌毛介导的脑膜炎奈瑟菌在内皮细胞上的粘附会诱导酪氨酰磷酸化，并在细菌菌落下方大量招募 ErbB2。然而，在受感染的细胞中，EGF 受体 ErbB3 或 ErbB4 的磷酸化状态和细胞定位均未受到影响。脑膜炎奈瑟菌诱导的 ErbB2 磷酸化为激酶 src 提供对接位点并导致其随后激活。特异性抑制 ErbB2 和/或 src 活性可减少细菌内化至内皮细胞，而不影响细菌诱导的肌动蛋白细胞骨架重组或 ErbB2 募集。此外，抑制肌动蛋白聚合和 ErbB2/src 途径完全阻止细菌进入。总而言之，我们的结果通过提供细菌诱导的 ErbB2 聚类导致 src 激酶磷酸化和激活的证据，为 ErbB2 功能提供了新的见解。该途径与细菌诱导的肌动蛋白细胞骨架重组相结合，是脑膜炎奈瑟菌有效内化至内皮细胞所必需的，这是使该病原体能够跨越宿主细胞屏障的重要过程。
ErbB2 is a receptor tyrosine kinase belonging to the family of epidermal growth factor (EGF) receptors which is generally involved in cell differentiation, proliferation, and tumor growth, and activated by heterodimerization with the other members of the family. We show here that type IV pilus–mediated adhesion of Neisseria meningitidis onto endothelial cells induces tyrosyl phosphorylation and massive recruitment of ErbB2 underneath the bacterial colonies. However, neither the phosphorylation status nor the cellular localization of the EGF receptors, ErbB3 or ErbB4, were affected in infected cells. ErbB2 phosphorylation induced by N. meningitidis provides docking sites for the kinase src and leads to its subsequent activation. Specific inhibition of either ErbB2 and/or src activity reduces bacterial internalization into endothelial cells without affecting bacteria-induced actin cytoskeleton reorganization or ErbB2 recruitment. Moreover, inhibition of both actin polymerization and the ErbB2/src pathway totally prevents bacterial entry. Altogether, our results provide new insight into ErbB2 function by bringing evidence of a bacteria-induced ErbB2 clustering leading to src kinase phosphorylation and activation. This pathway, in cooperation with the bacteria-induced reorganization of the actin cytoskeleton, is required for the efficient internalization of N. meningitidis into endothelial cells, an essential process enabling this pathogen to cross host cell barriers.
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