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Significance of filamin A in mTORC2 function in glioblastoma

Overview of attention for article published in Molecular Cancer, July 2015
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Title
Significance of filamin A in mTORC2 function in glioblastoma
Published in
Molecular Cancer, July 2015
DOI 10.1186/s12943-015-0396-z
Pubmed ID
Authors

Naphat Chantaravisoot, Piriya Wongkongkathep, Joseph A. Loo, Paul S. Mischel, Fuyuhiko Tamanoi

Abstract

Glioblastoma multiforme (GBM) is one of the most highly metastatic cancers. GBM has been associated with a high level of the mechanistic target of rapamycin complex 2 (mTORC2) activity. We aimed to observe roles of mTORC2 in GBM cells especially on actin cytoskeleton reorganization, cell migration and invasion, and further determine new important players involved in the regulation of these cellular processes. To further investigate the significance of mTORC2 in GBM, we treated GBM cells with PP242, an ATP-competitive inhibitor of mTOR, and used RICTOR siRNA to knock down mTORC2 activity. Effects on actin cytoskeleton, focal adhesion, migration, and invasion of GBM cells were examined. To gain insight into molecular basis of the mTORC2 effects on cellular cytoskeletal arrangement and motility/invasion, we affinity purified mTORC2 from GBM cells and identified proteins of interest by mass spectrometry. Characterization of the protein of interest was performed. In addition to the inhibition of mTORC2 activity, we demonstrated significant alteration of actin distribution as revealed by the use of phalloidin staining. Furthermore, vinculin staining was altered which suggests changes in focal adhesion. Inhibition of cell migration and invasion was observed with PP242. Two major proteins that are associated with this mTORC2 multiprotein complex were found. Mass spectrometry identified one of them as Filamin A (FLNA). Association of FLNA with RICTOR but not mTOR was demonstrated. Moreover, in vitro, purified mTORC2 can phosphorylate FLNA likewise its known substrate, AKT. In GBM cells, colocalization of FLNA with RICTOR was observed, and the overall amounts of FLNA protein as well as phosphorylated FLNA are high. Upon treatments of RICTOR siRNA or PP242, phosphorylated FLNA levels at the regulatory residue (Ser2152) decreased. This treatment also disrupted colocalization of Actin filaments and FLNA. Our results support FLNA as a new downstream effector of mTORC2 controlling GBM cell motility. This new mTORC2-FLNA signaling pathway plays important roles in motility and invasion of glioblastoma cells.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 54 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 2%
Brazil 1 2%
Unknown 52 96%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 10 19%
Researcher 8 15%
Student > Bachelor 5 9%
Professor > Associate Professor 4 7%
Student > Master 4 7%
Other 12 22%
Unknown 11 20%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 17 31%
Agricultural and Biological Sciences 7 13%
Medicine and Dentistry 7 13%
Neuroscience 2 4%
Immunology and Microbiology 1 2%
Other 3 6%
Unknown 17 31%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 10 July 2015.
All research outputs
#18,418,694
of 22,816,807 outputs
Outputs from Molecular Cancer
#1,291
of 1,721 outputs
Outputs of similar age
#189,294
of 263,464 outputs
Outputs of similar age from Molecular Cancer
#43
of 48 outputs
Altmetric has tracked 22,816,807 research outputs across all sources so far. This one is in the 11th percentile – i.e., 11% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,721 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 5.7. This one is in the 14th percentile – i.e., 14% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 263,464 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 16th percentile – i.e., 16% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 48 others from the same source and published within six weeks on either side of this one. This one is in the 4th percentile – i.e., 4% of its contemporaries scored the same or lower than it.