An RNAi screen of Rho signalling networks identifies RhoH as a regulator of Rac1 in prostate cancer cell migration
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 interferenc...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-03-01
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| Series: | BMC Biology |
| Online Access: | http://link.springer.com/article/10.1186/s12915-018-0489-4 |
| _version_ | 1818503980800540672 |
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| author | Virginia Tajadura-Ortega Ritu Garg Richard Allen Claudia Owczarek Michael D. Bright Samuel Kean Aisyah Mohd-Noor Anita Grigoriadis Timothy C. Elston Klaus M. Hahn Anne J. Ridley |
| author_facet | Virginia Tajadura-Ortega Ritu Garg Richard Allen Claudia Owczarek Michael D. Bright Samuel Kean Aisyah Mohd-Noor Anita Grigoriadis Timothy C. Elston Klaus M. Hahn Anne J. Ridley |
| author_sort | Virginia Tajadura-Ortega |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T21:31:02Z |
| format | Article |
| id | doaj.art-ff58e5f3ece74db8839b003b8eba8180 |
| institution | Directory Open Access Journal |
| issn | 1741-7007 |
| language | English |
| last_indexed | 2024-12-10T21:31:02Z |
| publishDate | 2018-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj.art-ff58e5f3ece74db8839b003b8eba81802022-12-22T01:32:48ZengBMCBMC Biology1741-70072018-03-0116112010.1186/s12915-018-0489-4An RNAi screen of Rho signalling networks identifies RhoH as a regulator of Rac1 in prostate cancer cell migrationVirginia Tajadura-Ortega0Ritu Garg1Richard Allen2Claudia Owczarek3Michael D. Bright4Samuel Kean5Aisyah Mohd-Noor6Anita Grigoriadis7Timothy C. Elston8Klaus M. Hahn9Anne J. Ridley10Randall Centre of Cell and Molecular Biophysics, King’s College LondonRandall Centre of Cell and Molecular Biophysics, King’s College LondonDepartment of Pharmacology, University of North Carolina at Chapel HillRandall Centre of Cell and Molecular Biophysics, King’s College LondonRandall Centre of Cell and Molecular Biophysics, King’s College LondonRandall Centre of Cell and Molecular Biophysics, King’s College LondonSchool of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s HospitalSchool of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s HospitalDepartment of Pharmacology, University of North Carolina at Chapel HillDepartment of Pharmacology, University of North Carolina at Chapel HillRandall Centre of Cell and Molecular Biophysics, King’s College LondonAbstract 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.http://link.springer.com/article/10.1186/s12915-018-0489-4 |
| spellingShingle | Virginia Tajadura-Ortega Ritu Garg Richard Allen Claudia Owczarek Michael D. Bright Samuel Kean Aisyah Mohd-Noor Anita Grigoriadis Timothy C. Elston Klaus M. Hahn Anne J. Ridley An RNAi screen of Rho signalling networks identifies RhoH as a regulator of Rac1 in prostate cancer cell migration BMC Biology |
| title | An RNAi screen of Rho signalling networks identifies RhoH as a regulator of Rac1 in prostate cancer cell migration |
| title_full | An RNAi screen of Rho signalling networks identifies RhoH as a regulator of Rac1 in prostate cancer cell migration |
| title_fullStr | An RNAi screen of Rho signalling networks identifies RhoH as a regulator of Rac1 in prostate cancer cell migration |
| title_full_unstemmed | An RNAi screen of Rho signalling networks identifies RhoH as a regulator of Rac1 in prostate cancer cell migration |
| title_short | An RNAi screen of Rho signalling networks identifies RhoH as a regulator of Rac1 in prostate cancer cell migration |
| title_sort | rnai screen of rho signalling networks identifies rhoh as a regulator of rac1 in prostate cancer cell migration |
| url | http://link.springer.com/article/10.1186/s12915-018-0489-4 |
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