Syntenin mediates SRC function in exosomal cell-to-cell communication.
Syntenin mediates SRC function in exosomal cell-to-cell communication.
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DOI：
10.1073/pnas.1713433114
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发表时间：
2017-11-21
影响因子：
11.1
通讯作者：
Zimmermann P
中科院分区：
文献类型：
--
作者：
Imjeti NS;Menck K;Egea-Jimenez AL;Lecointre C;Lembo F;Bouguenina H;Badache A;Ghossoub R;David G;Roche S;Zimmermann P
内体起源的病毒样纳米囊泡（或“外泌体”）是新近认识到的信号载体，细胞在包括癌症在内的各种系统性疾病中使用这些信号进行交流。然而，调节外泌体生物发生和活性的分子机制仍然不清楚。在这里，我们确定致癌蛋白 SRC 刺激装载有 Syntenin 和 Syndecans 的外泌体的分泌，这些外泌体是大量信号传导和粘附分子的已知共受体。 SRC 磷酸化多配聚糖和多肌联蛋白中保守的酪氨酸残基，并刺激它们的内体出芽。此外，SRC依赖性外泌体具有严格依赖于syntenin表达的前迁移活性。这项工作揭示了 SRC 在细胞间通讯中的功能以及外泌体生物发生和活性的机制，对病理生理学具有潜在的广泛影响。细胞质酪氨酸激酶 SRC 控制细胞生长、增殖、粘附和运动。目前的观点是，SRC 主要作用于细胞表面受体的下游，以控制细胞内信号级联。在这里，我们揭示了 SRC 通过控制外泌体的生物发生和活性在细胞间通讯中发挥作用。外泌体是来自内体来源的病毒样颗粒，可以重新编程受体细胞。通过功能获得和功能丧失研究，我们确定SRC刺激对内皮细胞具有前移活性的外泌体的分泌，并且syntenin对于SRC外泌体功能是必需的。从机制上讲，SRC 影响多聚糖胞吞作用和多聚糖内体出芽，ARF6 小 GTP 酶及其效应磷脂酶 D2 的上游，直接磷酸化多聚糖胞质结构域和多聚糖蛋白酪氨酸 46 的保守近膜 DEGSY 基序。我们的研究揭示了多聚糖蛋白外泌体支持的 SRC 在细胞与细胞通讯中的功能，这可能有助于肿瘤与宿主的相互作用。
Viral-like nanovesicles of endosomal origin, or “exosomes,” are newly recognized vehicles of signals that cells use to communicate, in various systemic diseases, including cancer. Yet the molecular mechanisms that regulate the biogenesis and activity of exosomes remain obscure. Here, we establish that the oncogenic protein SRC stimulates the secretion of exosomes loaded with syntenin and syndecans, known co-receptors for a plethora of signaling and adhesion molecules. SRC phosphorylates conserved tyrosine residues in the syndecans and syntenin and stimulates their endosomal budding. Moreover, SRC-dependent exosomes have a promigratory activity that strictly depends on syntenin expression. This work sheds light on a function of SRC in cell-to-cell communication and mechanisms of exosome biogenesis and activity, with potential broad impact for physiopathology. The cytoplasmic tyrosine kinase SRC controls cell growth, proliferation, adhesion, and motility. The current view is that SRC acts primarily downstream of cell-surface receptors to control intracellular signaling cascades. Here we reveal that SRC functions in cell-to-cell communication by controlling the biogenesis and the activity of exosomes. Exosomes are viral-like particles from endosomal origin that can reprogram recipient cells. By gain- and loss-of-function studies, we establish that SRC stimulates the secretion of exosomes having promigratory activity on endothelial cells and that syntenin is mandatory for SRC exosomal function. Mechanistically, SRC impacts on syndecan endocytosis and on syntenin–syndecan endosomal budding, upstream of ARF6 small GTPase and its effector phospholipase D2, directly phosphorylating the conserved juxtamembrane DEGSY motif of the syndecan cytosolic domain and syntenin tyrosine 46. Our study uncovers a function of SRC in cell–cell communication, supported by syntenin exosomes, which is likely to contribute to tumor–host interactions.
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DOI：
10.1073/pnas.0808171105
发表时间：
2008-10-14
影响因子：
11.1
作者：
Boukerche, Habib;Su, Zao-zhong;Fisher, Paul B.
通讯作者：
Fisher, Paul B.
影响因子：
9.8
作者：
Mineo, Marco;Garfield, Susan H.;Taverna, Simona;Flugy, Anna;De Leo, Giacomo;Alessandro, Riccardo;Kohn, Elise C.
通讯作者：
Kohn, Elise C.
影响因子：
7.2
作者：
Klumperman, Judith;Raposo, Graca
通讯作者：
Raposo, Graca
影响因子：
4
作者：
Lambaerts, Kathleen;Van Dyck, Stijn;Zimmermann, Pascale
通讯作者：
Zimmermann, Pascale
影响因子：
8
作者：
Boukerche, H.;Aissaoui, H.;Prevost, C.;Hirbec, H.;Das, S. K.;Su, Z-Z;Sarkar, D.;Fisher, P. B.
通讯作者：
Fisher, P. B.