Abstract

Cell migration is important for development and its aberrant regulation contributes to many diseases. The Scar/WAVE complex is essential for Arp2/3 mediated lamellipodia formation during mesenchymal cell migration and several coinciding signals activate it. However, so far, no direct negative regulators are known. Here we identify Nance-Horan Syndrome-like 1 protein (NHSL1) as a direct binding partner of the Scar/WAVE complex, which co-localise at protruding lamellipodia. This interaction is mediated by the Abi SH3 domain and two binding sites in NHSL1. Furthermore, active Rac binds to NHSL1 at two regions that mediate leading edge targeting of NHSL1. Surprisingly, NHSL1 inhibits cell migration through its interaction with the Scar/WAVE complex. Mechanistically, NHSL1 may reduce cell migration efficiency by impeding Arp2/3 activity, as measured in cells using a Arp2/3 FRET-FLIM biosensor, resulting in reduced F-actin density of lamellipodia, and consequently impairing the stability of lamellipodia protrusions.

Cell migration is essential for many physiological processes. Its deregulation causes cancer metastasis and it is not well understood how it is tightly controlled. We identify NHSL1 as a negative regulator of actin nucleating Scar/WAVE-Arp2/3 complexes, cell protrusion stability, and cell migration.

Details

Title
Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration
Author
Ah-Lai, Law 1 ; Shamsinar, Jalal 2 ; Pallett Tommy 2   VIAFID ORCID Logo  ; Mosis Fuad 2 ; Ahmad, Guni 2 ; Brayford, Simon 3 ; Yolland Lawrence 3 ; Marcotti Stefania 3   VIAFID ORCID Logo  ; Levitt, James A 4 ; Poland, Simon P 4 ; Rowe-Sampson, Maia 5 ; Jandke Anett 6   VIAFID ORCID Logo  ; Köchl, Robert 7   VIAFID ORCID Logo  ; Pula Giordano 8 ; Ameer-Beg, Simon M 4   VIAFID ORCID Logo  ; Stramer Brian Marc 3   VIAFID ORCID Logo  ; Krause, Matthias 2   VIAFID ORCID Logo 

1  King’s College London, Krause Group, Randall Centre for Cell and Molecular Biophysics, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); School of Life Sciences, University of Bedfordshire, Luton, UK (GRID:grid.15034.33) (ISNI:0000 0000 9882 7057) 
2  King’s College London, Krause Group, Randall Centre for Cell and Molecular Biophysics, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
3  King’s College London, Stramer Group, Randall Centre for Cell and Molecular Biophysics, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
4  King’s College London, Ameer-Beg Group, Richard Dimbleby Cancer Research Laboratories, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
5  King’s College London, Krause Group, Randall Centre for Cell and Molecular Biophysics, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); King’s College London, Stramer Group, Randall Centre for Cell and Molecular Biophysics, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
6  King’s College London, Krause Group, Randall Centre for Cell and Molecular Biophysics, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); The Francis Crick Institute, Immunosurveillance Laboratory, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830) 
7  King’s College London, School of Immunology and Microbial Sciences, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
8  King’s College London, Krause Group, Randall Centre for Cell and Molecular Biophysics, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg (UKE), Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-25916-6
ProQuest document ID
2576852393
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.