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

Author:

Butt Umar12,Khan Meraj H.2,Pouwels Jeroen2,Westermarck Jukka12ORCID

Affiliation:

1. Institute of Biomedicine, University of Turku 1 , Turku, FI-20014 , Finland

2. Turku Bioscience Centre, University of Turku, and Åbo Akademi University 2 , FI-20520, Turku , Finland

Abstract

ABSTRACT 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.

Funder

Academy of Finland

Syöpäsäätiö

Sigrid Juséliuksen Säätiö

Suomen Kulttuurirahasto

K. Albin Johanssons Stiftelse

Turun Yliopisto

Publisher

The Company of Biologists

Subject

Cell Biology

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