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

Woroniuk, A. et al. (2018) STEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap. Nature Communications, 9, 2124. (doi: 10.1038/s41467-018-04404-4) (PMID:29844364) (PMCID:PMC5974301)

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.

• Item Type: Articles
• Additional Information: This work was supported by Cancer Research UK (grant number C5759/A12328), MRC (grant number MR/L007495/1) and Worldwide Cancer Research (WCR 16–0379). Work in the laboratory of K.M.H. is supported by the NIH, grant number: GMR35GM122596.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Strathdee, Mr Douglas and Sansom, Professor Owen
• Authors: Woroniuk, A., Porter, A., White, G., Newman, D. T., Diamantopoulou, Z., Waring, T., Rooney, C., Strathdee, D., Marston, D. J., Hahn, K. M., Sansom, O. J., Zech, T., and Malliri, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Nature Communications 9: 2124
• Publisher Policy: Reproduced under a Creative Commons License