Extracellular signal-regulated kinase regulates RhoA activation and tumor cell plasticity by inhibiting guanine exchange factor H1 activity

Anne von Thun, Christian Preisinger, Oliver Rath, Juliane P. Schwarz, Chris Ward, Naser Monsefi, Javier Rodríguez, Amaya Garcia-Munoz, Marc Birtwistle, Willy Bienvenut, Kurt I. Anderson, Walter Kolch, Alex von Kriegsheima

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

In certain Ras mutant cell lines, the inhibition of extracellular signal-regulated kinase (ERK) signaling increases RhoA activity and inhibits cell motility, which was attributed to a decrease in Fra-1 levels. Here we report a Fra-1-independent augmentation of RhoA signaling during short-term inhibition of ERK signaling. Using mass spectrometry-based proteomics, we identified guanine exchange factor H1 (GEF-H1) as mediating this effect. ERK binds to the Rho exchange factor GEF-H1 and phosphorylates it on S959, causing inhibition of GEF-H1 activity and a consequent decrease in RhoA activity. Knockdown experiments and expression of a nonphosphorylatable S959A GEF-H1 mutant showed that this site is crucial in regulating cell motility and invasiveness. Thus, we identified GEF-H1 as a critical ERK effector that regulates motility, cell morphology, and invasiveness.

Original languageEnglish
Pages (from-to)4526-4537
Number of pages12
JournalMolecular and Cellular Biology
Volume33
Issue number22
DOIs
StatePublished - 15 Nov 2013

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