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SHARPIN S146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis

Pouwels Jeroen; Khan Meraj H; Butt Umar; Westermarck Jukka

SHARPIN S146 phosphorylation mediates ARP2/3 interaction, cancer cell invasion and metastasis

Pouwels Jeroen
Khan Meraj H
Butt Umar
Westermarck Jukka
Katso/Avaa
jcs260627.pdf (4.311Mb)
Lataukset: 

Company of Biologists
doi:10.1242/jcs.260627
URI
https://journals.biologists.com/jcs/article/135/20/jcs260627/277281/SHARPIN-S146-phosphorylation-mediates-ARP2-3
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2022121571599
Tiivistelmä

SHARPIN is involved in several cellular processes and promotes cancer progression. However, how the choice between different functions of SHARPIN is post-translationally regulated is unclear. Here, we characterized SHARPIN phosphorylation by mass spectrometry and in vitro kinase assay. Focusing on S131 and S146, we demonstrate that they have a role in SHARPIN-ARP2/3 complex interaction, but play no role in integrin inhibition or LUBAC activation. Consistent with its novel role in ARP2/3 regulation, S146 phosphorylation of SHARPIN promoted lamellipodia formation. We also demonstrate that SHARPIN S146 phosphorylation-mediated ARP2/3 interaction is sensitive to inhibition of ERK1/2 or reactivation of protein phosphatase 2A (PP2A). Notably, CRISPR/Cas9-mediated knockout of SHARPIN abrogated three-dimensional (3D) invasion of several cancer cell lines. The 3D invasion of cancer cells was rescued by overexpression of the wild-type SHARPIN, but not by SHARPIN S146A mutant. Finally, we demonstrate that inhibition of phosphorylation at S146 significantly reduces in vivo metastasis in a zebrafish model. Collectively, these results map SHARPIN phosphorylation sites and identify S146 as a novel phosphorylation switch defining ARP2/3 interaction and cancer cell invasion. This article has an associated First Person interview with the first author of the paper.

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