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Phosphorylation of chemoattractant receptors regulates chemotaxis, actin reorganization and signal relay

Migratory cells, including mammalian leukocytes and Dictyostelium, use G-protein-coupled receptor (GPCR) signaling to regulate MAPK/ERK, PI3K, TORC2/AKT, adenylyl cyclase and actin polymerization, which collectively direct chemotaxis. Upon ligand binding, mammalian GPCRs are phosphorylated at cytopl...

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Autores principales: Brzostowski, Joseph A., Sawai, Satoshi, Rozov, Orr, Liao, Xin-hua, Imoto, Daisuke, Parent, Carole A., Kimmel, Alan R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795335/
https://www.ncbi.nlm.nih.gov/pubmed/23902692
http://dx.doi.org/10.1242/jcs.122952
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author Brzostowski, Joseph A.
Sawai, Satoshi
Rozov, Orr
Liao, Xin-hua
Imoto, Daisuke
Parent, Carole A.
Kimmel, Alan R.
author_facet Brzostowski, Joseph A.
Sawai, Satoshi
Rozov, Orr
Liao, Xin-hua
Imoto, Daisuke
Parent, Carole A.
Kimmel, Alan R.
author_sort Brzostowski, Joseph A.
collection PubMed
description Migratory cells, including mammalian leukocytes and Dictyostelium, use G-protein-coupled receptor (GPCR) signaling to regulate MAPK/ERK, PI3K, TORC2/AKT, adenylyl cyclase and actin polymerization, which collectively direct chemotaxis. Upon ligand binding, mammalian GPCRs are phosphorylated at cytoplasmic residues, uncoupling G-protein pathways, but activating other pathways. However, connections between GPCR phosphorylation and chemotaxis are unclear. In developing Dictyostelium, secreted cAMP serves as a chemoattractant, with extracellular cAMP propagated as oscillating waves to ensure directional migratory signals. cAMP oscillations derive from transient excitatory responses of adenylyl cyclase, which then rapidly adapts. We have studied chemotactic signaling in Dictyostelium that express non-phosphorylatable cAMP receptors and show through chemotaxis modeling, single-cell FRET imaging, pure and chimeric population wavelet quantification, biochemical analyses and TIRF microscopy, that receptor phosphorylation is required to regulate adenylyl cyclase adaptation, long-range oscillatory cAMP wave production and cytoskeletal actin response. Phosphorylation defects thus promote hyperactive actin polymerization at the cell periphery, misdirected pseudopodia and the loss of directional chemotaxis. Our data indicate that chemoattractant receptor phosphorylation is required to co-regulate essential pathways for migratory cell polarization and chemotaxis. Our results significantly extend the understanding of the function of GPCR phosphorylation, providing strong evidence that this evolutionarily conserved mechanism is required in a signal attenuation pathway that is necessary to maintain persistent directional movement of Dictyostelium, neutrophils and other migratory cells.
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spelling pubmed-37953352013-11-01 Phosphorylation of chemoattractant receptors regulates chemotaxis, actin reorganization and signal relay Brzostowski, Joseph A. Sawai, Satoshi Rozov, Orr Liao, Xin-hua Imoto, Daisuke Parent, Carole A. Kimmel, Alan R. J Cell Sci Research Article Migratory cells, including mammalian leukocytes and Dictyostelium, use G-protein-coupled receptor (GPCR) signaling to regulate MAPK/ERK, PI3K, TORC2/AKT, adenylyl cyclase and actin polymerization, which collectively direct chemotaxis. Upon ligand binding, mammalian GPCRs are phosphorylated at cytoplasmic residues, uncoupling G-protein pathways, but activating other pathways. However, connections between GPCR phosphorylation and chemotaxis are unclear. In developing Dictyostelium, secreted cAMP serves as a chemoattractant, with extracellular cAMP propagated as oscillating waves to ensure directional migratory signals. cAMP oscillations derive from transient excitatory responses of adenylyl cyclase, which then rapidly adapts. We have studied chemotactic signaling in Dictyostelium that express non-phosphorylatable cAMP receptors and show through chemotaxis modeling, single-cell FRET imaging, pure and chimeric population wavelet quantification, biochemical analyses and TIRF microscopy, that receptor phosphorylation is required to regulate adenylyl cyclase adaptation, long-range oscillatory cAMP wave production and cytoskeletal actin response. Phosphorylation defects thus promote hyperactive actin polymerization at the cell periphery, misdirected pseudopodia and the loss of directional chemotaxis. Our data indicate that chemoattractant receptor phosphorylation is required to co-regulate essential pathways for migratory cell polarization and chemotaxis. Our results significantly extend the understanding of the function of GPCR phosphorylation, providing strong evidence that this evolutionarily conserved mechanism is required in a signal attenuation pathway that is necessary to maintain persistent directional movement of Dictyostelium, neutrophils and other migratory cells. The Company of Biologists 2013-10-15 /pmc/articles/PMC3795335/ /pubmed/23902692 http://dx.doi.org/10.1242/jcs.122952 Text en © 2013. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Brzostowski, Joseph A.
Sawai, Satoshi
Rozov, Orr
Liao, Xin-hua
Imoto, Daisuke
Parent, Carole A.
Kimmel, Alan R.
Phosphorylation of chemoattractant receptors regulates chemotaxis, actin reorganization and signal relay
title Phosphorylation of chemoattractant receptors regulates chemotaxis, actin reorganization and signal relay
title_full Phosphorylation of chemoattractant receptors regulates chemotaxis, actin reorganization and signal relay
title_fullStr Phosphorylation of chemoattractant receptors regulates chemotaxis, actin reorganization and signal relay
title_full_unstemmed Phosphorylation of chemoattractant receptors regulates chemotaxis, actin reorganization and signal relay
title_short Phosphorylation of chemoattractant receptors regulates chemotaxis, actin reorganization and signal relay
title_sort phosphorylation of chemoattractant receptors regulates chemotaxis, actin reorganization and signal relay
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795335/
https://www.ncbi.nlm.nih.gov/pubmed/23902692
http://dx.doi.org/10.1242/jcs.122952
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