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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 |
| ISSN: | 0021-9525 |
| Publisher: | Rockefeller University Press |
| Volume: | 216 |
| Number: | 12 |
| 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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