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An AMPK phosphoregulated RhoGEF feedback loop tunes cortical flow–driven amoeboid migration in vivo

Development, morphogenesis, immune system function, and cancer metastasis rely on the ability of cells to move through diverse tissues. To dissect migratory cell behavior in vivo, we developed cell type–specific imaging and perturbation techniques for Drosophila primordial germ cells (PGCs). We find...

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Detalles Bibliográficos
Autores principales: Lin, Benjamin, Luo, Jonathan, Lehmann, Ruth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9473612/
https://www.ncbi.nlm.nih.gov/pubmed/36103538
http://dx.doi.org/10.1126/sciadv.abo0323
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author Lin, Benjamin
Luo, Jonathan
Lehmann, Ruth
author_facet Lin, Benjamin
Luo, Jonathan
Lehmann, Ruth
author_sort Lin, Benjamin
collection PubMed
description Development, morphogenesis, immune system function, and cancer metastasis rely on the ability of cells to move through diverse tissues. To dissect migratory cell behavior in vivo, we developed cell type–specific imaging and perturbation techniques for Drosophila primordial germ cells (PGCs). We find that PGCs use global, retrograde cortical actin flows for orientation and propulsion during guided developmental homing. PGCs use RhoGEF2, a RhoA-specific RGS-RhoGEF, as a dose-dependent regulator of cortical flow through a feedback loop requiring its conserved PDZ and PH domains for membrane anchoring and local RhoA activation. This feedback loop is regulated for directional migration by RhoGEF2 availability and requires AMPK rather than canonical Gα(12/13) signaling. AMPK multisite phosphorylation of RhoGEF2 near a conserved EB1 microtubule-binding SxIP motif releases RhoGEF2 from microtubule-dependent inhibition. Thus, we establish the mechanism by which global cortical flow and polarized RhoA activation can be dynamically adapted during natural cell navigation in a changing environment.
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spelling pubmed-94736122022-09-29 An AMPK phosphoregulated RhoGEF feedback loop tunes cortical flow–driven amoeboid migration in vivo Lin, Benjamin Luo, Jonathan Lehmann, Ruth Sci Adv Biomedicine and Life Sciences Development, morphogenesis, immune system function, and cancer metastasis rely on the ability of cells to move through diverse tissues. To dissect migratory cell behavior in vivo, we developed cell type–specific imaging and perturbation techniques for Drosophila primordial germ cells (PGCs). We find that PGCs use global, retrograde cortical actin flows for orientation and propulsion during guided developmental homing. PGCs use RhoGEF2, a RhoA-specific RGS-RhoGEF, as a dose-dependent regulator of cortical flow through a feedback loop requiring its conserved PDZ and PH domains for membrane anchoring and local RhoA activation. This feedback loop is regulated for directional migration by RhoGEF2 availability and requires AMPK rather than canonical Gα(12/13) signaling. AMPK multisite phosphorylation of RhoGEF2 near a conserved EB1 microtubule-binding SxIP motif releases RhoGEF2 from microtubule-dependent inhibition. Thus, we establish the mechanism by which global cortical flow and polarized RhoA activation can be dynamically adapted during natural cell navigation in a changing environment. American Association for the Advancement of Science 2022-09-14 /pmc/articles/PMC9473612/ /pubmed/36103538 http://dx.doi.org/10.1126/sciadv.abo0323 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Lin, Benjamin
Luo, Jonathan
Lehmann, Ruth
An AMPK phosphoregulated RhoGEF feedback loop tunes cortical flow–driven amoeboid migration in vivo
title An AMPK phosphoregulated RhoGEF feedback loop tunes cortical flow–driven amoeboid migration in vivo
title_full An AMPK phosphoregulated RhoGEF feedback loop tunes cortical flow–driven amoeboid migration in vivo
title_fullStr An AMPK phosphoregulated RhoGEF feedback loop tunes cortical flow–driven amoeboid migration in vivo
title_full_unstemmed An AMPK phosphoregulated RhoGEF feedback loop tunes cortical flow–driven amoeboid migration in vivo
title_short An AMPK phosphoregulated RhoGEF feedback loop tunes cortical flow–driven amoeboid migration in vivo
title_sort ampk phosphoregulated rhogef feedback loop tunes cortical flow–driven amoeboid migration in vivo
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9473612/
https://www.ncbi.nlm.nih.gov/pubmed/36103538
http://dx.doi.org/10.1126/sciadv.abo0323
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