ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles.

By Vandhana Muralidharan-Chari, James W. Clancy, Carolyn Plou, M. Romao, P. Chavrier, G. Raposo, C. D’Souza-Schorey. Current Biology, 2009

823 citations recorded by the source corpus.

BACKGROUND Increased mitogen-activated protein kinase (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. RESULTS 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 extracellular matrix (ECM) is facilitated by microvesicle-associated integrin receptors. CONCLUSIONS 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.

Subfields: Cancer Research, Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7344a6eca9077ecbee296a34c0ac02f280151794

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. C. Théry
2. G. Raposo
3. Marina Colombo
4. Hina Kalra
5. Suresh Mathivanan
6. M. Tkach
7. M. Wood
8. P. Vader

In Cell Biology

1. C. Théry
2. G. Raposo
3. Marina Colombo
4. Suresh Mathivanan
5. M. Wood

In Molecular Biology

1. C. Théry
2. G. Raposo
3. Marina Colombo
4. Hina Kalra
5. Suresh Mathivanan
6. P. Vader
7. G. Drummen
8. J. Kowal

Citations in the corpus

• Microvesicles: mediators of extracellular communication during cancer progression (2010, background): “During abscission, contractile machinery within the cleavage furrow draws the opposing membranes together before pinching off the membrane connection and separating the daughter cells (Muralidharan-Chari et al., 2009a; Schweitzer and D’SouzaSchorey, 2004).”
• Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies (2013, neutral): “For instance, actinmyosin interactions appear critical to the formation of all four types of EVs [66, 85, 100, 115].”
• Exosomes in cancer development, metastasis, and immunity (2019, background): “The mechanism of microvesicle and ApoEV release are not well known, but ARF6 [32] and the small GTPase RHOA [33] were reported to control microvesicle shedding; caspase-3 was required for detachment of ApoEVs from the membrane [34].”
• Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. (2014, methodology): “Larger vesicles, by contrast, can be visualized by fluorescence microscopy, and shedding from cells of vesicles of 0.5 µm to a few micrometers in diameter has been observed by video microscopy (Di Vizio et al. 2012, MacKenzie et al. 2001, Muralidharan-Chari et al. 2009).”
• Focus on Extracellular Vesicles: Introducing the Next Small Big Thing (2016, background): “In particular the GTP-binding protein ADP-ribosylation factor 6 (ARF6) has been alleged to play a role in ectosome secretion [26].”
• Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression (2018, background): “One of the most well-described regulators of MV shedding is ADP-ribosylation factor 6 (ARF6), a member belonging to the Ras superfamily of small GTPases (67, 68).”
• Exosomes (2010, background): “In a first attempt to understand this process better, the group of D’schouza-Schorey convincingly showed that activation of ARF6 is critical for an actomyosin-based membrane ‘abscission mechanism’ that regulates the shedding of selected cellular components from the plasma membrane.(20) Although thes”