Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth
Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth
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DOI：
10.1128/mcb.25.15.6391-6403.2005
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发表时间：
2005-08-01
影响因子：
5.3
通讯作者：
Chiarugi, P
中科院分区：
文献类型：
--
作者：
Giannoni, E;Buricchi, F;Chiarugi, P
Src 酪氨酸激酶是粘附反应的核心成分，是细胞扩散到细胞外基质上所必需的。整联蛋白连接引起的其他细胞内信使包括活性氧，它充当细胞骨架重排和细胞扩散的协同介质。我们报告说，整合素连接后，酪氨酸激酶 Src 被氧化并激活。 Src 显示早期激活阶段，与粘着斑形成同时并主要由 Tyr527 去磷酸化驱动，以及晚期激活阶段，伴随活性氧产生、细胞扩散和整合素引发的激酶氧化。此外，我们的结果表明，活性氧是体外和体内 v-Src 致瘤特性的关键介质，因为抗氧化剂治疗和氧化剂敏感的 C245A 和 C487A Src 突变体都大大降低了侵袭性、血清非依赖性和锚定非依赖性生长以及肿瘤发生。因此，我们提出，除了已知的磷酸化/去磷酸化回路外，在细胞附着到细胞外基质和肿瘤发生过程中，Src活性的氧化还原调节也是必需的。
Src tyrosine kinases are central components of adhesive responses and are required for cell spreading onto the extracellular matrix. Among other intracellular messengers elicited by integrin ligation are reactive oxygen species, which act as synergistic mediators of cytoskeleton rearrangement and cell spreading. We report that after integrin ligation, the tyrosine kinase Src is oxidized and activated. Src displays an early activation phase, concurrent with focal adhesion formation and driven mainly by Tyr527 dephosphorylation, and a late phase, concomitant with reactive oxygen species production, cell spreading, and integrin-elicited kinase oxidation. In addition, our results suggest that reactive oxygen species are key mediators of in vitro and in vivo v-Src tumorigenic properties, as both antioxidant treatments and the oxidant-in sensitive C245A and C487A Src mutants greatly decrease invasivity, serum-independent and anchorage-independent growth, and tumor onset. Therefore we propose that, in addition to the known phosphorylation/dephosphorylation circuitry, redox regulation of Src activity is required during both cell attachment to the extracellullar matrix and tumorigenesis.