Leucine-rich repeat-containing G-protein coupled receptor 5/GPR49 activates G12/13-Rho GTPase pathway |
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Authors: | Mi So Kwon Bi-oh Park Ho Min Kim Sunhong Kim |
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Institution: | 1. Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon, 363-883, Korea 2. Biomolecular Science Major, University of Science and Technology, Daejeon, 305-350, Korea 3. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, Korea
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Abstract: | Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5/GPR49) is highly expressed in adult stem cells of various tissues, such as intestine, hair follicles, and stomach. LGR5 is also overexpressed in some colon and ovarian tumors. Recent reports show that R-spondin (RSPO) family ligands bind to and activate LGR5, enhancing canonical Wnt signaling via the interaction with LRP5/6 and Frizzled. The identity of heterotrimeric G-proteins coupled to LGR5, however, remains unclear. Here, we show that Rho GTPase is a downstream target of LGR5. Overexpression of LGR5 induced SRF-RE luciferase activity, a reporter of Rho signaling. RSPOs, ligands for LGR4, LGR5, and LGR6, however, did not induce SRF-RE reporter activity in the presence of LGR5. Consistently, LGR5-induced activity of the SRF-RE reporter was inhibited by Rho inhibitor C3 transferase and RhoA N19 mutant, and knockdown of Gα12/13 genes blocked the reporter activity induced by LGR5. In addition, focal adhesion kinase, NF-κB and c-fos, targets of Rho GTPase, were shown to be regulated by LGR5. Here, we have demonstrated, for the first time, that LGR5 is coupled to the Rho pathway through G12/13 signaling. |
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Keywords: | FAK G12/13 LGR5 NFkappaB Rho |
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