title: Extracellular signal-regulated kinase regulates RhoA activation and tumor cell plasticity by inhibiting guanine exchange factor H1 activity.
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.
authors.affiliation: The Beatson Institute for Cancer Research, Glasgow, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: von Thun
authors.forename: Christian
authors.initials: C
authors.lastname: Preisinger
authors.forename: Oliver
authors.initials: O
authors.lastname: Rath
authors.forename: Juliane P
authors.initials: JP
authors.lastname: Schwarz
authors.forename: Chris
authors.initials: C
authors.lastname: Ward
authors.forename: Naser
authors.initials: N
authors.lastname: Monsefi
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez
authors.forename: Amaya
authors.initials: A
authors.lastname: Garcia-Munoz
authors.forename: Marc
authors.initials: M
authors.lastname: Birtwistle
authors.forename: Willy
authors.initials: W
authors.lastname: Bienvenut
authors.forename: Kurt I
authors.initials: KI
authors.lastname: Anderson
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.forename: Alex
authors.initials: A
authors.lastname: von Kriegsheim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D016760:Proto-Oncogene Proteins c-fos; D064067:Rho Guanine Nucleotide Exchange Factors; D020742:rhoA GTP-Binding Protein; D000099169:Fos-Related Antigen 1; C577356:ARHGEF2 protein, human
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