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

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  • معلومة اضافية
    • المصدر:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101190720 Publication Model: Electronic Cited Medium: Internet ISSN: 1741-7007 (Electronic) Linking ISSN: 17417007 NLM ISO Abbreviation: BMC Biol Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: [London] : BioMed Central, c2003-
    • الموضوع:
      Cell Movement/*genetics ; Genetic Testing/*methods ; Prostatic Neoplasms/*genetics ; RNA Interference/*physiology ; Transcription Factors/*genetics ; rac1 GTP-Binding Protein/*genetics ; rho GTP-Binding Proteins/*genetics; Animals ; Biomarkers, Tumor/analysis ; Biomarkers, Tumor/genetics ; COS Cells ; Chlorocebus aethiops ; Early Detection of Cancer/methods ; HT29 Cells ; Humans ; MCF-7 Cells ; Male ; Prostatic Neoplasms/diagnosis ; Transcription Factors/analysis ; rac1 GTP-Binding Protein/analysis ; rho GTP-Binding Proteins/analysis
    • نبذة مختصرة :
      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.
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    • Grant Information:
      R01-GM079271 United States NH NIH HHS; R01 GM079271 United States GM NIGMS NIH HHS; C41786/A132 United Kingdom CRUK_ Cancer Research UK; C6620/A15961 United Kingdom CRUK_ Cancer Research UK; U01-EB018816 United States NH NIH HHS; R35 GM122596 United States GM NIGMS NIH HHS; PO1-GM103723 United States NH NIH HHS; U01 EB018816 United States EB NIBIB NIH HHS; 15961 United Kingdom CRUK_ Cancer Research UK; P01 GM103723 United States GM NIGMS NIH HHS; C6220/A8833 United Kingdom CRUK_ Cancer Research UK; P41 EB002025 United States EB NIBIB NIH HHS
    • الرقم المعرف:
      0 (Biomarkers, Tumor)
      0 (RAC1 protein, human)
      0 (RhoH protein, human)
      0 (Transcription Factors)
      EC 3.6.5.2 (rac1 GTP-Binding Protein)
      EC 3.6.5.2 (rho GTP-Binding Proteins)
    • الموضوع:
      Date Created: 20180308 Date Completed: 20190325 Latest Revision: 20240922
    • الموضوع:
      20250114
    • الرقم المعرف:
      PMC5840776
    • الرقم المعرف:
      10.1186/s12915-018-0489-4
    • الرقم المعرف:
      29510700