Journal
JOURNAL OF CELL SCIENCE
Volume 135, Issue 20, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.260627
Keywords
FRET; Invasion; LUBAC; MDA-MB-231; Integrin; Phosphorylation
Categories
Funding
- Academy of Finland
- Syopasaatio
- Sigrid Juseliuksen Saatio
- Suomen Kulttuurirahasto
- Turun Yliopisto
- K. Albin Johanssons Stiftelse
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This study identifies the role of SHARPIN phosphorylation in cellular processes and cancer progression, with a specific focus on the S146 phosphorylation and its regulation of the ARP2/3 complex interaction, promoting cancer cell invasion.
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.
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