TY - JOUR
T1 - Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration
AU - Krause, Matthias
AU - Stramer, Brian
AU - Ameer-Beg, Simon
AU - Poland, Simon
AU - Levitt, James
AU - Marcotti, Stefania
AU - Köchl, Robert
AU - Pallett, Tommy
AU - Law, Ah-Lai
AU - Binti Abd Jalal, Sham
AU - Mosis, Fuad
N1 - Funding Information:
We thank Laura Machesky (Beatson Institute, Glasgow, UK) for reagents. Andrew Jamieson and Gaudenz Danuser (UT Southwestern, USA) for providing the Windowing MATLAB script. William Barrell (King’s College London, UK) for qPCR training. F.M. was supported by a Medical Research Council (MRC) studentship. T.P. was supported by an Engineering and Physical Sciences Research Council (EPSRC) studentship. S.J. was supported by a Malaysian Public Service Department (PSD) studentship. This work was supported by grants from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 681808) (B.M.S.), CRUK Comprehensive Cancer Centre block grant (S.M.A.-B), Medical Research Council (MRC) (S.M.A.-B.), Richard Dimbleby Cancer Trust (S.M.A.-B.), Wellcome Trust (107859/Z/15/Z) (B.M.S.) (082907/Z/07/Z) (M.K.), the Biotechnology and Biological Science Research Council, UK (BB/F011431/1; BB/J000590/1; BB/N000226/1; BB/R015953/1) (M.K.) and Cancer Research UK (S.A.-B.) (C22104/A7155) (M.K.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/9/28
Y1 - 2021/9/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85116036077&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25916-6
DO - 10.1038/s41467-021-25916-6
M3 - Article
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5687
ER -