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Nat Commun. 2018 May 29;9(1):2124. doi: 10.1038/s41467-018-04404-4.

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

Author information

1
Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG, UK.
2
Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK.
3
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
4
Department of Pharmacology, University of North Carolina, Chapel Hill, NC, 27599-7365, USA.
5
Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1BD, UK.
6
Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG, UK. Angeliki.Malliri@cruk.manchester.ac.uk.

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.

PMID:
29844364
PMCID:
PMC5974301
DOI:
10.1038/s41467-018-04404-4
[Indexed for MEDLINE]
Free PMC Article

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