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  • Title: Extracellular signal-regulated kinase regulates RhoA activation and tumor cell plasticity by inhibiting guanine exchange factor H1 activity.
    Author: von Thun A, Preisinger C, Rath O, Schwarz JP, Ward C, Monsefi N, Rodríguez J, Garcia-Munoz A, Birtwistle M, Bienvenut W, Anderson KI, Kolch W, von Kriegsheim A.
    Journal: Mol Cell Biol; 2013 Nov; 33(22):4526-37. PubMed ID: 24043311.
    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.
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