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Curr Biol. 2018 May 21;28(10):1570-1584.e6. doi: 10.1016/j.cub.2018.03.068. Epub 2018 May 3.

Quantitative Control of GPCR Organization and Signaling by Endocytosis in Epithelial Morphogenesis.

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Aix Marseille Université, CNRS, IBDM - UMR7288, Turing Centre for Living Systems, Marseille, France.
National Centre for Biological Sciences, TIFR, Bangalore 560065, India.
Aix Marseille Université, CNRS, IBDM - UMR7288, Turing Centre for Living Systems, Marseille, France; Collège de France, 11 Place Marcelin Berthelot, Paris, France. Electronic address:


Tissue morphogenesis arises from controlled cell deformations in response to cellular contractility. During Drosophila gastrulation, apical activation of the actomyosin networks drives apical constriction in the invaginating mesoderm and cell-cell intercalation in the extending ectoderm. Myosin II (MyoII) is activated by cell-surface G protein-coupled receptors (GPCRs), such as Smog and Mist, that activate G proteins, the small GTPase Rho1, and the kinase Rok. Quantitative control over GPCR and Rho1 activation underlies differences in deformation of mesoderm and ectoderm cells. We show that GPCR Smog activity is concentrated on two different apical plasma membrane compartments, i.e., the surface and plasma membrane invaginations. Using fluorescence correlation spectroscopy, we probe the surface of the plasma membrane, and we show that Smog homo-clusters in response to its activating ligand Fog. Endocytosis of Smog is regulated by the kinase Gprk2 and β-arrestin-2 that clears active Smog from the plasma membrane. When Fog concentration is high or endocytosis is low, Smog rearranges in homo-clusters and accumulates in plasma membrane invaginations that are hubs for Rho1 activation. Lastly, we find higher Smog homo-cluster concentration and numerous apical plasma membrane invaginations in the mesoderm compared to the ectoderm, indicative of reduced endocytosis. We identify that dynamic partitioning of active Smog at the surface of the plasma membrane or plasma membrane invaginations has a direct impact on Rho1 signaling. Plasma membrane invaginations accumulate high Rho1-guanosine triphosphate (GTP) suggesting they form signaling centers. Thus, Fog concentration and Smog endocytosis form coupled regulatory processes that regulate differential Rho1 and MyoII activation in the Drosophila embryo.


G protein-coupled receptor; G protein-coupled receptor kinase; acto-myosin contractility; endocytosis; epithelial morphogenesis; fluorescence correlation spectroscopy; gastrulation; β-arrestin


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