Integrin endosomal signalling suppresses anoikis.
Integrin endosomal signalling suppresses anoikis.
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DOI：
10.1038/ncb3250
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发表时间：
2015-11
影响因子：
21.3
通讯作者：
Ivaska J
中科院分区：
文献类型：
--
作者：
Alanko J;Mai A;Jacquemet G;Schauer K;Kaukonen R;Saari M;Goud B;Ivaska J
含有整合素的粘着斑（FA）通过质膜传递细胞外信号以调节细胞粘附、信号传导和存活。虽然已知整合素经历连续的胞内/胞外运输，但胞吞运输对整合素诱导的信号的潜在影响是未知的。在这里，我们证明了整合素信号传导并不局限于细胞-ECM粘附，并确定了一个内体信号传导平台，支持整合素信号传导远离质膜。我们发现，活性粘着斑激酶（FAK），一个既定的标志物整合素ECM下游信号，本地化与活性整合素的内涵体。整合素内吞作用正调节粘附诱导的FAK活化，其是早期内体抗原-1（EEA 1）和小GTdR Rab 21依赖性的。FAK直接结合到纯化的内体上并在其上被激活，表明内吞作用在增强不同的整合素下游信号传导事件中的作用。最后，内体整合素信号传导有助于癌症相关过程，如失巢凋亡抗性、锚定独立性和转移。整合素是细胞表面粘附受体的异源二聚体，其功能是整合细胞外基质（extracellular matrix，ECM）驱动的信号、细胞骨架和细胞信号装置，在粘附过程中，整合素触发质膜近端的大的机械感应和信号传递蛋白簇的形成，称为“粘附体”。此外，整合素经历恒定的内吞运输以促进粘着斑周转、细胞迁移、侵袭和胞质分裂。对于其他受体系统，已经确定内吞膜运输调节细胞表面分子的生物利用度，因此调节受体启动信号的强度和/或特异性。虽然活性整联蛋白及其配体已经在内体中被检测到，并且增加的整联蛋白再循环至质膜有助于增强共运输受体酪氨酸激酶的信号传导，但仍不清楚内吞的活性整联蛋白是否在内体中信号传导。在这里，我们证明了整合素信号传导并不局限于如前所述的局灶性粘连，并且内吞作用对于完整的ECM诱导的整合素介导的ERK、AKT和FAK信号传导是必要的。我们发现FAK直接结合到纯化的内体上，并且可以在纯化的内体上被激活。此外，FAK的FERM结构域能够结合纯化的含有整合素的内体，表明整合素信号传导复合物在活性整合素内化后在内体上组装的潜力。重要的是，FAK是锚定非依赖性生长和抑制失巢凋亡所必需的。整合素内体信号传导与正常细胞失巢凋亡敏感性降低和乳腺癌细胞锚定非依赖性生长和转移相关。
Integrin containing focal adhesions (FAs) transmit extracellular signals across the plasma membrane to modulate cell adhesion, signalling and survival. Although integrins are known to undergo continuous endo/exocytic traffic, potential impact of endocytic traffic on integrin-induced signals is unknown. Here, we demonstrate that integrin signalling is not restricted to cell-ECM adhesions and identify an endosomal signalling platform that supports integrin signalling away from the plasma membrane. We show that active focal adhesion kinase (FAK), an established marker of integrin-ECM downstream signalling, localises with active integrins on endosomes. Integrin endocytosis positively regulates adhesion-induced FAK activation, which is early endosome antigen-1 (EEA1) and small GTPase Rab21 dependent. FAK binds directly to purified endosomes and becomes activated on them, suggesting a role for endocytosis in enhancing distinct integrin downstream signalling events. Finally, endosomal integrin signalling contributes to cancer-related processes such as anoikis resistance, anchorage-independence and metastasis. Integrins are heterodimeric cell surface adhesion receptors functioning as integrators of the extra-cellular matrix (ECM) driven cues, the cellular cytoskeleton and the cellular signalling apparatus.Upon adhesion, integrins trigger the formation of plasma-membrane proximal large mechanosensing and signal-transmitting protein clusters depicted as “adhesomes”. In addition, integrins undergo constant endocytic traffic to facilitate focal adhesion turnover, cell migration, invasion and cytokinesis. For other receptor systems it is well established that endocytic membrane traffic regulates bioavailability of cell-surface molecules and therefore the intensity and/or specificity of receptor-initiated signals. Although active integrins and their ligands have been detected in endosomes and increased integrin recycling to the plasma membrane contributes to enhanced signalling of co-trafficked receptor tyrosine kinases it has remained unclear whether endocytosed active integrins signal in endosomes. Here, we demonstrate that integrin signalling is not restricted to focal adhesions as previously described and that endocytosis is necessary for full ECM-induced, integrin mediated ERK, AKT and FAK signalling. We find that FAK binds directly to and can become activated on purified endosomes. Moreover, the FERM-domain of FAK is able to bind purified integrin containing endosomes, suggesting the potential for integrin signalling complexes to assemble on endosomes after internalization of active integrins. Importantly, FAK is required for anchorage-independent growth and suppression of anoikis. Integrin endosomal signalling correlates with reduced anoikis sensitivity in normal cells and anchorage-independent growth and metastasis in breast cancer cells.