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

Anna Woroniuk, Andrew Porter, Gavin White, Daniel T. Newman, Zoi Diamantopoulou, Thomas Waring, Claire Rooney, Douglas Strathdee, Daniel J. Marston, Klaus M. Hahn, Owen J. Sansom, Tobias Zech and Angeliki Malliri ()
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Anna Woroniuk: The University of Manchester
Andrew Porter: The University of Manchester
Gavin White: The University of Manchester
Daniel T. Newman: University of Liverpool
Zoi Diamantopoulou: The University of Manchester
Thomas Waring: University of Liverpool
Claire Rooney: The University of Manchester
Douglas Strathdee: Garscube Estate, Switchback Road
Daniel J. Marston: University of North Carolina
Klaus M. Hahn: University of North Carolina
Owen J. Sansom: Garscube Estate, Switchback Road
Tobias Zech: University of Liverpool
Angeliki Malliri: The University of Manchester

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04404-4

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