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Receptor tyrosine kinase activation of RhoA is mediated by AKT phosphorylation of DLC1

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Item Type:Article
Title:Receptor tyrosine kinase activation of RhoA is mediated by AKT phosphorylation of DLC1
Creators Name:Tripathi, B.K. and Grant, T. and Qian, X. and Zhou, M. and Mertins, P. and Wang, D. and Papageorge, A.G. and Tarasov, S.G. and Hunter, K.W. and Carr, S.A. and Lowy, D.R.
Abstract:We report several receptor tyrosine kinase (RTK) ligands increase RhoA-guanosine triphosphate (GTP) in untransformed and transformed cell lines and determine this phenomenon depends on the RTKs activating the AKT serine/threonine kinase. The increased RhoA-GTP results from AKT phosphorylating three serines (S298, S329, and S567) in the DLC1 tumor suppressor, a Rho GTPase-activating protein (RhoGAP) associated with focal adhesions. Phosphorylation of the serines, located N-terminal to the DLC1 RhoGAP domain, induces strong binding of that N-terminal region to the RhoGAP domain, converting DLC1 from an open, active dimer to a closed, inactive monomer. That binding, which interferes with the interaction of RhoA-GTP with the RhoGAP domain, reduces the hydrolysis of RhoA-GTP, the binding of other DLC1 ligands, and the colocalization of DLC1 with focal adhesions and attenuates tumor suppressor activity. DLC1 is a critical AKT target in DLC1-positive cancer because AKT inhibition has potent antitumor activity in the DLC1-positive transgenic cancer model and in a DLC1-positive cancer cell line but not in an isogenic DLC1-negative cell line.
Keywords:Binding Sites, Cell Line, Cell Movement, Crystalline Lens, Epithelial Cells, Fibroblasts, Focal Adhesions, GTPase-Activating Proteins, Gene Expression Regulation, Guanosine Triphosphate, HEK293 Cells, HeLa Cells, Hydrolysis, Phosphorylation, Protein Binding, Protein Domains, Protein Multimerization, Proto-Oncogene Proteins c-akt, Signal Transduction, Tumor Suppressor Proteins, rhoA GTP-Binding Protein
Source:Journal of Cell Biology
Publisher:Rockefeller University Press
Page Range:4255
Date:4 December 2017
Official Publication:https://doi.org/10.1083/jcb.201703105
PubMed:View item in PubMed

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