Cargando…

The small GTPase HRas shapes local PI3K signals through positive feedback and regulates persistent membrane extension in migrating fibroblasts

Self-amplification of phosphoinositide 3-kinase (PI3K) signaling is believed to regulate asymmetric membrane extension and cell migration, but the molecular organization of the underlying feedback circuit is elusive. Here we use an inducible approach to synthetically activate PI3K and interrogate th...

Descripción completa

Detalles Bibliográficos
Autores principales: Thevathasan, Jervis Vermal, Tan, Elisabeth, Zheng, Hui, Lin, Yu-Chun, Li, Yang, Inoue, Takanari, Fivaz, Marc
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708728/
https://www.ncbi.nlm.nih.gov/pubmed/23676667
http://dx.doi.org/10.1091/mbc.E12-12-0905
_version_ 1782276647022493696
author Thevathasan, Jervis Vermal
Tan, Elisabeth
Zheng, Hui
Lin, Yu-Chun
Li, Yang
Inoue, Takanari
Fivaz, Marc
author_facet Thevathasan, Jervis Vermal
Tan, Elisabeth
Zheng, Hui
Lin, Yu-Chun
Li, Yang
Inoue, Takanari
Fivaz, Marc
author_sort Thevathasan, Jervis Vermal
collection PubMed
description Self-amplification of phosphoinositide 3-kinase (PI3K) signaling is believed to regulate asymmetric membrane extension and cell migration, but the molecular organization of the underlying feedback circuit is elusive. Here we use an inducible approach to synthetically activate PI3K and interrogate the feedback circuitry governing self-enhancement of 3′-phosphoinositide (3-PI) signals in NIH3T3 fibroblasts. Synthetic activation of PI3K initially leads to uniform production of 3-PIs at the plasma membrane, followed by the appearance of asymmetric and highly amplified 3-PI signals. A detailed spatiotemporal analysis shows that local self-amplifying 3-PI signals drive rapid membrane extension with remarkable directional persistence and initiate a robust migratory response. This positive feedback loop is critically dependent on the small GTPase HRas. Silencing of HRas abrogates local amplification of 3-PI signals upon synthetic PI3K activation and results in short-lived protrusion events that do not support cell migration. Finally, our data indicate that this feedback circuit is likely to operate during platelet-derived growth factor–induced random cell migration. We conclude that positive feedback between PI3K and HRas is essential for fibroblasts to spontaneously self-organize and generate a productive migratory response in the absence of spatial cues.
format Online
Article
Text
id pubmed-3708728
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher The American Society for Cell Biology
record_format MEDLINE/PubMed
spelling pubmed-37087282013-09-30 The small GTPase HRas shapes local PI3K signals through positive feedback and regulates persistent membrane extension in migrating fibroblasts Thevathasan, Jervis Vermal Tan, Elisabeth Zheng, Hui Lin, Yu-Chun Li, Yang Inoue, Takanari Fivaz, Marc Mol Biol Cell Articles Self-amplification of phosphoinositide 3-kinase (PI3K) signaling is believed to regulate asymmetric membrane extension and cell migration, but the molecular organization of the underlying feedback circuit is elusive. Here we use an inducible approach to synthetically activate PI3K and interrogate the feedback circuitry governing self-enhancement of 3′-phosphoinositide (3-PI) signals in NIH3T3 fibroblasts. Synthetic activation of PI3K initially leads to uniform production of 3-PIs at the plasma membrane, followed by the appearance of asymmetric and highly amplified 3-PI signals. A detailed spatiotemporal analysis shows that local self-amplifying 3-PI signals drive rapid membrane extension with remarkable directional persistence and initiate a robust migratory response. This positive feedback loop is critically dependent on the small GTPase HRas. Silencing of HRas abrogates local amplification of 3-PI signals upon synthetic PI3K activation and results in short-lived protrusion events that do not support cell migration. Finally, our data indicate that this feedback circuit is likely to operate during platelet-derived growth factor–induced random cell migration. We conclude that positive feedback between PI3K and HRas is essential for fibroblasts to spontaneously self-organize and generate a productive migratory response in the absence of spatial cues. The American Society for Cell Biology 2013-07-15 /pmc/articles/PMC3708728/ /pubmed/23676667 http://dx.doi.org/10.1091/mbc.E12-12-0905 Text en © 2013 Thevathasan et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Thevathasan, Jervis Vermal
Tan, Elisabeth
Zheng, Hui
Lin, Yu-Chun
Li, Yang
Inoue, Takanari
Fivaz, Marc
The small GTPase HRas shapes local PI3K signals through positive feedback and regulates persistent membrane extension in migrating fibroblasts
title The small GTPase HRas shapes local PI3K signals through positive feedback and regulates persistent membrane extension in migrating fibroblasts
title_full The small GTPase HRas shapes local PI3K signals through positive feedback and regulates persistent membrane extension in migrating fibroblasts
title_fullStr The small GTPase HRas shapes local PI3K signals through positive feedback and regulates persistent membrane extension in migrating fibroblasts
title_full_unstemmed The small GTPase HRas shapes local PI3K signals through positive feedback and regulates persistent membrane extension in migrating fibroblasts
title_short The small GTPase HRas shapes local PI3K signals through positive feedback and regulates persistent membrane extension in migrating fibroblasts
title_sort small gtpase hras shapes local pi3k signals through positive feedback and regulates persistent membrane extension in migrating fibroblasts
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3708728/
https://www.ncbi.nlm.nih.gov/pubmed/23676667
http://dx.doi.org/10.1091/mbc.E12-12-0905
work_keys_str_mv AT thevathasanjervisvermal thesmallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT tanelisabeth thesmallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT zhenghui thesmallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT linyuchun thesmallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT liyang thesmallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT inouetakanari thesmallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT fivazmarc thesmallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT thevathasanjervisvermal smallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT tanelisabeth smallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT zhenghui smallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT linyuchun smallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT liyang smallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT inouetakanari smallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts
AT fivazmarc smallgtpasehrasshapeslocalpi3ksignalsthroughpositivefeedbackandregulatespersistentmembraneextensioninmigratingfibroblasts