An RNAi screen of Rho signalling networks identifies RhoH as a regulator of Rac1 in prostate cancer cell migration Public Deposited

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Creator
  • Garg, Ritu
    • Other Affiliation: Randall Centre of Cell and Molecular Biophysics, King’s College London, London, UK
  • Bright, Michael D
    • Other Affiliation: Randall Centre of Cell and Molecular Biophysics, King’s College London, London, UK; Present address: Institute for Cancer Research, Sutton, UK
  • Hahn, Klaus
    • Affiliation: School of Medicine, Department of Pharmacology
  • Elston, Timothy
    • Affiliation: School of Medicine, Department of Pharmacology
  • Ridley, Anne J
    • Other Affiliation: Randall Centre of Cell and Molecular Biophysics, King’s College London, London, UK; School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
  • Kean, Samuel
    • Other Affiliation: Randall Centre of Cell and Molecular Biophysics, King’s College London, London, UK
  • Grigoriadis, Anita
    • Other Affiliation: School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Hospital, London, UK
  • Tajadura-Ortega, Virginia
    • Other Affiliation: Randall Centre of Cell and Molecular Biophysics, King’s College London, London, UK; School of Cardiovascular Medicine and Sciences, King’s College London, London, UK
  • Allen, Richard
    • Affiliation: School of Medicine, Department of Pharmacology
    • Other Affiliation: Present address: Internal Medicine Research Unit, Pfizer Inc, Cambridge, USA
  • Mohd-Noor, Aisyah
    • Other Affiliation: School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Hospital, London, UK
  • Owczarek, Claudia
    • Other Affiliation: Randall Centre of Cell and Molecular Biophysics, King’s College London, London, UK
Abstract
  • Abstract Background Cell migration is essential for development and tissue repair, but it also contributes to disease. Rho GTPases regulate cell migration, but a comprehensive analysis of how each Rho signalling component affects migration has not been carried out. Results Through an RNA interference screen, and using a prostate cancer cell line, we find that approximately 25% of Rho network components alter migration. Some genes enhance migration while others decrease basal and/or hepatocyte growth factor-stimulated migration. Surprisingly, we identify RhoH as a screen hit. RhoH expression is normally restricted to haematopoietic cells, but we find it is expressed in multiple epithelial cancer cell lines. High RhoH expression in samples from prostate cancer patients correlates with earlier relapse. RhoH depletion reduces cell speed and persistence and decreases migratory polarity. Rac1 activity normally localizes to the front of migrating cells at areas of dynamic membrane movement, but in RhoH-depleted cells active Rac1 is localised around the whole cell periphery and associated with membrane regions that are not extending or retracting. RhoH interacts with Rac1 and with several p21-activated kinases (PAKs), which are Rac effectors. Similar to RhoH depletion, PAK2 depletion increases cell spread area and reduces cell migration. In addition, RhoH depletion reduces lamellipodium extension induced by PAK2 overexpression. Conclusions We describe a novel role for RhoH in prostate cancer cell migration. We propose that RhoH promotes cell migration by coupling Rac1 activity and PAK2 to membrane protrusion. Our results also suggest that RhoH expression levels correlate with prostate cancer progression.
Date of publication
Identifier
  • doi:10.1186/s12915-018-0489-4
Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Ridley et al.
Language
  • English
Bibliographic citation
  • BMC Biology. 2018 Mar 06;16(1):29
Publisher
  • BioMed Central
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