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

von Thun, A. et al. (2013) Extracellular signal-regulated kinase regulates RhoA activation and tumor cell plasticity by inhibiting guanine exchange factor H1 activity. Molecular and Cellular Biology, 33(22), pp. 4526-4537. (doi: 10.1128/MCB.00585-13)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bienvenut, Dr Willy and Kolch, Prof Walter and Schwarz, Ms Juliana and Anderson, Professor Kurt and Rath, Dr Oliver and Preisinger, Dr Christian
• Authors: von Thun, A., Preisinger, C., Rath, O., Schwarz, J.P., Ward, C., Monsefi, N., Rodriguez, J., Garcia-Munoz, A., Birtwistle, M., Bienvenut, W., Anderson, K.I., Kolch, W., and von Kriegsheim, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular and Cellular Biology
• ISSN: 0270-7306
• ISSN (Online): 1098-5549