STEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap.

Nature Communications
Anna WoroniukAngeliki Malliri

Abstract

The perinuclear actin cap is an important cytoskeletal structure that regulates nuclear morphology and re-orientation during front-rear polarisation. The mechanisms regulating the actin cap are currently poorly understood. Here, we demonstrate that STEF/TIAM2, a Rac1 selective guanine nucleotide exchange factor, localises at the nuclear envelope, co-localising with the key perinuclear proteins Nesprin-2G and Non-muscle myosin IIB (NMMIIB), where it regulates perinuclear Rac1 activity. We show that STEF depletion reduces apical perinuclear actin cables (a phenotype rescued by targeting active Rac1 to the nuclear envelope), increases nuclear height and impairs nuclear re-orientation. STEF down-regulation also reduces perinuclear pMLC and decreases myosin-generated tension at the nuclear envelope, suggesting that STEF-mediated Rac1 activity regulates NMMIIB activity to promote stabilisation of the perinuclear actin cap. Finally, STEF depletion decreases nuclear stiffness and reduces expression of TAZ-regulated genes, indicating an alteration in mechanosensing pathways as a consequence of disruption of the actin cap.

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Citations

Nov 30, 2019·Nature Reviews. Cancer·Gautier FollainJacky G Goetz
Sep 2, 2020·The Journal of Cell Biology·Claudia BaumannRabindranath De La Fuente
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Nov 14, 2021·Proceedings of the National Academy of Sciences of the United States of America·Huimin ZhangLi Bai
Jul 1, 2021·Cold Spring Harbor Perspectives in Biology·Yekaterina A Miroshnikova, Sara A Wickström

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Methods Mentioned

BETA
GTPase
GTPases
nucleotide exchange
biosensor
proximity ligation
co-immunoprecipitation
pull-down
immunoprecipitation
ELISA
Fluorescence

Software Mentioned

Metamorph
Prism
Cell Profiler
Leica
Genewiz
ImageJ
JPK Imaging Processing
Harmony
Imaris
LAS AF Lite

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