4.5 Article

RhoB regulates uPAR signalling

Journal

JOURNAL OF CELL SCIENCE
Volume 125, Issue 10, Pages 2369-2380

Publisher

COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.091579

Keywords

Rho GTPases; Cell migration; Signal transduction; uPA; uPAR

Categories

Funding

  1. Cancer Research UK [C6620/A8833]
  2. Italian Ministero dell'Istruzione, dell'Universita e della Ricerca [2007YJAP2M]
  3. Associazione Italiana per la Ricerca sul Cancro [IG 4714]
  4. European Molecular Biology Organization [ASTF 270.00-2007]
  5. Federation of the Societies of Biochemistry and Molecular Biology

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Urokinase-type plasminogen activator (uPA) and its receptor, uPAR, play important roles in promoting cancer cell adhesion, migration and invasion. Rho GTPases are key coordinators of these processes; the Rho GTPase Rac1 has previously been implicated in uPA-and/or uPAR-induced migratory or morphological cell responses. We used RNAi to deplete 12 different Rho GTPases to screen for effects on uPA-stimulated migration, and found that depletion of RhoB significantly reduces uPA-induced migration and invasion of prostate carcinoma cells. RhoB depletion did not affect the expression or surface levels of uPAR but reduced the uPAR-induced increase in levels of several integrins and inhibited uPAR signalling to the actin regulator cofilin, the cell-adhesion signal-transduction adaptor molecule paxillin and the serine/threonine kinase Akt. uPAR rapidly activated RhoB and increased RhoB expression. RhoB depletion also reduced cell adhesion to and spreading on vitronectin, which is a uPAR ligand. This correlated with decreased association between integrins and uPAR and reduced integrin beta 1 activity. Our results indicate that RhoB is a key regulator of uPAR signalling in cell adhesion, migration and invasion.

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