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The stem cell-expressed receptor Lgr5 possesses canonical and functionally active molecular determinants critical to β-arrestin-2 recruitment.

Publication ,  Journal Article
Snyder, JC; Rochelle, LK; Barak, LS; Caron, MG
Published in: PLoS One
2013

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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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

12

Start / End Page

e84476

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Protein Structure, Tertiary
  • Humans
  • HEK293 Cells
  • General Science & Technology
  • Arrestins
  • Amino Acid Motifs
 

Citation

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Snyder, J. C., Rochelle, L. K., Barak, L. S., & Caron, M. G. (2013). The stem cell-expressed receptor Lgr5 possesses canonical and functionally active molecular determinants critical to β-arrestin-2 recruitment. PLoS One, 8(12), e84476. https://doi.org/10.1371/journal.pone.0084476
Snyder, Joshua C., Lauren K. Rochelle, Larry S. Barak, and Marc G. Caron. “The stem cell-expressed receptor Lgr5 possesses canonical and functionally active molecular determinants critical to β-arrestin-2 recruitment.PLoS One 8, no. 12 (2013): e84476. https://doi.org/10.1371/journal.pone.0084476.
Snyder, Joshua C., et al. “The stem cell-expressed receptor Lgr5 possesses canonical and functionally active molecular determinants critical to β-arrestin-2 recruitment.PLoS One, vol. 8, no. 12, 2013, p. e84476. Pubmed, doi:10.1371/journal.pone.0084476.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

12

Start / End Page

e84476

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Protein Structure, Tertiary
  • Humans
  • HEK293 Cells
  • General Science & Technology
  • Arrestins
  • Amino Acid Motifs