ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles.
ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles.
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DOI：
10.1016/j.cub.2009.09.059
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发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
D'Souza-Schorey C
中科院分区：
文献类型：
--
作者：
Muralidharan-Chari V;Clancy J;Plou C;Romao M;Chavrier P;Raposo G;D'Souza-Schorey C
MAPK信号传导增加、小GT3活化、细胞骨架重排和蛋白酶定向靶向细胞外基质降解位点都伴随肿瘤细胞侵袭的过程。一些研究表明，小GTP结合蛋白ARF 6参与了肿瘤细胞的侵袭，尽管ARF 6促进这一过程的分子基础尚不清楚。我们表明，ARF 6 GTP/GDP循环调节蛋白酶负载的质膜衍生的微泡从肿瘤细胞释放到周围环境中。为了使微囊泡脱落，磷脂酶D的ARF 6-GTP依赖性活化促进细胞外信号调节激酶（ERK）向质膜的募集，在质膜中ERK进而磷酸化并活化肌球蛋白轻链激酶（MLCK）。MLCK介导的MLC磷酸化是微囊泡释放所必需的。ARF 6活化的抑制伴随着PKC介导的MLC磷酸化，其阻断微泡脱落。蛋白质货物似乎被选择性地分选到微泡中，并且通过微泡相关的整合素受体促进与ECM的粘附。肿瘤细胞中的微泡脱落通过基于肌动球蛋白的膜脱落机制发生，该机制由ARF 6上的核苷酸循环调节。微泡脱落似乎释放选定的细胞组分，特别是那些参与细胞粘附和运动，进入周围环境。这些发现表明，ARF 6活化和微泡的蛋白水解活性都被认为与肿瘤进展直接相关，可能作为疾病的生物标志物。
Increased MAPK signaling, small GTPase activation, cytoskeletal rearrangements and the directed targeting of proteases to sites of extracellular matrix degradation, all accompany the process of tumor cell invasion. Several studies have implicated the small GTP-binding protein, ARF6, in tumor cell invasion although the molecular basis by which ARF6 facilitates this process is unclear. We show that the ARF6 GTP/GDP cycle regulates the release of protease-loaded plasma membrane-derived microvesicles from tumor cells into the surrounding environment. To enable microvesicle shedding, ARF6-GTP dependent activation of phospholipase D promotes the recruitment of the extracellular signal-regulated kinase (ERK) to the plasma membrane where in turn, ERK phosphorylates and activates myosin light chain kinase (MLCK). MLCK-mediated MLC phosphorylation is required for microvesicle release. Inhibition of ARF6 activation is accompanied by PKC-mediated phosphorylation of MLC, which blocks microvesicle shedding. Protein cargo appears to be selectively sorted into microvesicles and adhesion to the ECM is facilitated by microvesicle-associated integrin receptors. Microvesicle shedding in tumor cells occurs via an actomyosin-based membrane abscission mechanism that is regulated by nucleotide cycling on ARF6. Microvesicle shedding appears to release selected cellular components, particularly those involved in cell adhesion and motility, into the surrounding environment. These findings suggest that ARF6 activation and the proteolytic activities of microvesicles both of which are thought to correlate directly with tumor progression, could potentially serve as biomarkers for disease.
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影响因子：
11.4
作者：
Bravo-Cordero, Jose J.;Marrero-Diaz, Raquel;Montoya, Maria C.
通讯作者：
Montoya, Maria C.
DOI：
10.1083/jcb.146.1.149
发表时间：
1999-07-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Nguyen DH;Catling AD;Webb DJ;Sankovic M;Walker LA;Somlyo AV;Weber MJ;Gonias SL
通讯作者：
Gonias SL
影响因子：
11.2
作者：
Muralidharan-Chari V;Hoover H;Clancy J;Schweitzer J;Suckow MA;Schroeder V;Castellino FJ;Schorey JS;D'Souza-Schorey C
通讯作者：
D'Souza-Schorey C
影响因子：
11.2
作者：
Hu B;Shi B;Jarzynka MJ;Yiin JJ;D'Souza-Schorey C;Cheng SY
通讯作者：
Cheng SY
影响因子：
3.3
作者：
Jovanovic, OA;Brown, FD;Donaldson, JG
通讯作者：
Donaldson, JG