β1 integrin regulates Arg to promote invadopodial maturation and matrix degradation.
β1 integrin regulates Arg to promote invadopodial maturation and matrix degradation.
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DOI：
10.1091/mbc.e12-12-0908
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发表时间：
2013-06
影响因子：
3.3
通讯作者：
Condeelis J
中科院分区：
文献类型：
--
作者：
Beaty BT;Sharma VP;Bravo-Cordero JJ;Simpson MA;Eddy RJ;Koleske AJ;Condeelis J
β1 整合素是入侵足成熟的主要调节因子。研究表明，β1 整合素介导的粘附是一个关键的上游开关，可诱导 Arg 依赖性皮质蛋白磷酸化、肌动蛋白聚合以及 MMP 募集至侵袭伪足以实现细胞外基质降解。 β1 整合素已被证明可促进多种肿瘤模型的转移，包括乳腺癌、卵巢癌、胰腺癌和皮肤癌；然而，人们对它的作用机制知之甚少。被称为侵袭伪足的侵袭性膜突起被认为在转移过程中促进细胞外基质降解和内渗。先前的工作表明β1整合素定位于侵袭足，但其在调节侵袭足功能中的作用尚未得到很好的表征。我们发现β1整合素对于二维和三维基质中成熟的、具有降解能力的侵袭伪足的形成是必需的，但对于转移性人乳腺癌细胞中侵袭伪足前体的形成是可有可无的。 β1 整合素在入侵足前体成熟过程中被激活，强制 β1 整合素激活可提高入侵足基质蛋白水解率。此外，β1 整合素与酪氨酸激酶 Arg 相互作用，刺激 cortactin 在酪氨酸 421 上的 Arg 依赖性磷酸化。用小干扰 RNA 沉默 β1 整合素完全消除了入侵伪足中 Arg 依赖性 cortactin 磷酸化和 cofilin 依赖性倒刺末端的形成，导致成熟细胞的数量和稳定性显着下降。 侵袭伪足。这些结果描述了 β1 整合素在控制转移性肿瘤细胞中肌动蛋白聚合依赖性侵袭足成熟和基质降解中的基本作用。
β1 integrin is a major regulator of invadopodium maturation. Studies reveal that β1 integrin–mediated adhesion is a key upstream switch that induces Arg-dependent cortactin phosphorylation, actin polymerization, and MMP recruitment to invadopodia for extracellular matrix degradation. β1 integrin has been shown to promote metastasis in a number of tumor models, including breast, ovarian, pancreatic, and skin cancer; however, the mechanism by which it does so is poorly understood. Invasive membrane protrusions called invadopodia are believed to facilitate extracellular matrix degradation and intravasation during metastasis. Previous work showed that β1 integrin localizes to invadopodia, but its role in regulating invadopodial function has not been well characterized. We find that β1 integrin is required for the formation of mature, degradation-competent invadopodia in both two- and three-dimensional matrices but is dispensable for invadopodium precursor formation in metastatic human breast cancer cells. β1 integrin is activated during invadopodium precursor maturation, and forced β1 integrin activation enhances the rate of invadopodial matrix proteolysis. Furthermore, β1 integrin interacts with the tyrosine kinase Arg and stimulates Arg-dependent phosphorylation of cortactin on tyrosine 421. Silencing β1 integrin with small interfering RNA completely abrogates Arg-dependent cortactin phosphorylation and cofilin-dependent barbed-end formation at invadopodia, leading to a significant decrease in the number and stability of mature invadopodia. These results describe a fundamental role for β1 integrin in controlling actin polymerization–dependent invadopodial maturation and matrix degradation in metastatic tumor cells.