Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Kwon, Mi So; Park, Bi-Oh; Kim, Ho Min; Kim, Sunhong

doi:10.1007/s10059-013-0173-z

Cited by 17 publications

(16 citation statements)

References 46 publications

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“…In addition to the 7-TM bundle, Lgr5 contains canonical “DRY”, “NPXXY”, and “SSS” serine cluster motifs (Figure 1 and Figure 2). Moreover, during review of our manuscript, a single report was published indicating that Lgr5 may couple to the heterotrimeric G protein alpha subunits G 12/13 [54]. Therefore, these recent data, together with the multiple lines of structural, biochemical, and cell biological evidence that we present here, indicate that Lgr5 possesses the capacity for classical GPCR behavior.…”

Section: Discussionsupporting

confidence: 61%

The Stem Cell-Expressed Receptor Lgr5 Possesses Canonical and Functionally Active Molecular Determinants Critical to β-arrestin-2 Recruitment

et al. 2013

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Lgr5 is a membrane protein related to G protein-coupled receptors (GPCR)s whose expression identifies stem cells in multiple tissues and is strongly correlated with cancer. Despite the recent identification of endogenous ligands for Lgr5, its mode of signaling remains enigmatic. The ability to couple to G proteins and βarrestins are classical molecular behaviors of GPCRs that have yet to be observed for Lgr5. Therefore, the goal of this study was to determine if Lgr5 can engage a classical GPCR behavior and elucidate the molecular determinants of this process. Structural analysis of Lgr5 revealed several motifs consistent with its ability to recruit βarr2. Among them, a “SSS” serine cluster located at amino acid position 873-875 within the C-terminal tail (C-tail), is in a region consistent with other GPCRs that bind βarr2 with high-affinity. To test its functionality, a ligand-independent βarr2 translocation assay was implemented. We show that Lgr5 recruits βarr2 and that the “SSS” amino acids (873-875) are absolutely critical to this process. We also demonstrate that for full efficacy, this cluster requires other Lgr5 C-tail serines that were previously shown to be important for constitutive and βarr2 independent internalization of Lgr5. These data are proof of principle that a classical GPCR behavior can be manifested by Lgr5. The existence of alternative ligands or missing effectors of Lgr5 that scaffold this classical GPCR behavior and the downstream signaling pathways engaged should be considered. Characterizing Lgr5 signaling will be invaluable for assessing its role in tissue maintenance, repair, and disease.

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Section: Discussionsupporting

confidence: 61%

The Stem Cell-Expressed Receptor Lgr5 Possesses Canonical and Functionally Active Molecular Determinants Critical to β-arrestin-2 Recruitment

et al. 2013

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“…So far, no direct evidence indicates that the RSPO proteins regulate the cAMP-PKA-ATF4 pathway through the LGR4 receptor. Recently, it was also demonstrated that overexpression of the LGR5 receptor induced the G 12/13 -Rho GTPase pathway independently of RSPOs (45). Therefore, future investigation of whether the deficits in myogenic differentiation observed in Lgr4-KD cells is also linked to the disruption of the RSPO-independent GPCR pathway is warranted.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Follistatin Gene by RSPO-LGR4 Signaling via Activation of the WNT/β-Catenin Pathway in Skeletal Myogenesis

Han

Jin

Tan

et al. 2014

Molecular and Cellular Biology

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WNT signaling plays multiple roles in skeletal myogenesis during gestation and postnatal stages. The R-spondin (RSPO) family of secreted proteins and their cognate receptors, members of leucine-rich repeat-containing G protein-coupled receptor (LGR) family, have emerged as new regulatory components of the WNT signaling pathway. We previously showed that RSPO2 promoted myogenic differentiation via activation of WNT/␤-catenin signaling in mouse myoblast C2C12 cells in vitro. However, the molecular mechanism by which RSPO2 regulates myogenic differentiation is unknown. Herein, we show that depletion of the LGR4 receptor severely disrupts myogenic differentiation and significantly diminishes the response to RSPO2 in C2C12 cells, showing a requirement of LGR4 in RSPO signaling during myogenic differentiation. We identify the transforming growth factor ␤ (TGF-␤) antagonist follistatin (Fst) as a key mediator of RSPO-LGR4 signaling in myogenic differentiation. We further demonstrate that Fst is a direct target of the WNT/␤-catenin pathway. Activation and inactivation of ␤-catenin induced and inhibited Fst expression, respectively, in both C2C12 cells and mouse embryos. Specific TCF/LEF1 binding sites within the promoter and intron 1 region of the Fst gene were required for RSPO2 and WNT/␤-catenin-induced Fst expression. This study uncovers a molecular cross talk between WNT/␤-catenin and TGF-␤ signaling pivotal in myogenic differentiation.

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“…Finally, C3 was studied in cell division and apoptosis [80,81]. In more recent studies C3 was used to delineate the signaling induced by adiponectin [82], leptin [83], and the G protein-coupled receptor GPR49 [84].…”

Section: C3-like Adp-ribosyltransferasesmentioning

confidence: 99%

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Schmidt

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The Comprehensive Sourcebook of Bacterial Protein Toxins

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Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Cited by 17 publications

References 46 publications

The Stem Cell-Expressed Receptor Lgr5 Possesses Canonical and Functionally Active Molecular Determinants Critical to β-arrestin-2 Recruitment

The Stem Cell-Expressed Receptor Lgr5 Possesses Canonical and Functionally Active Molecular Determinants Critical to β-arrestin-2 Recruitment

Regulation of the Follistatin Gene by RSPO-LGR4 Signaling via Activation of the WNT/β-Catenin Pathway in Skeletal Myogenesis

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