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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., Grant, T., Qian, X., Zhou, M., Mertins, P., Wang, D., Papageorge, A.G., Tarasov, S.G., Hunter, K.W., 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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