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PI3Kβ links integrin activation and PI(3,4)P(2) production during invadopodial maturation

The invasion of tumor cells from the primary tumor is mediated by invadopodia, actin-rich protrusive organelles that secrete matrix metalloproteases and degrade the extracellular matrix. This coupling between protrusive activity and matrix degradation facilitates tumor invasion. We previously report...

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Autores principales: Erami, Zahra, Heitz, Samantha, Bresnick, Anne R., Backer, Jonathan M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741064/
https://www.ncbi.nlm.nih.gov/pubmed/31318314
http://dx.doi.org/10.1091/mbc.E19-03-0182
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author Erami, Zahra
Heitz, Samantha
Bresnick, Anne R.
Backer, Jonathan M.
author_facet Erami, Zahra
Heitz, Samantha
Bresnick, Anne R.
Backer, Jonathan M.
author_sort Erami, Zahra
collection PubMed
description The invasion of tumor cells from the primary tumor is mediated by invadopodia, actin-rich protrusive organelles that secrete matrix metalloproteases and degrade the extracellular matrix. This coupling between protrusive activity and matrix degradation facilitates tumor invasion. We previously reported that the PI3Kβ isoform of PI 3-kinase, which is regulated by both receptor tyrosine kinases and G protein–coupled receptors, is required for invasion and gelatin degradation in breast cancer cells. We have now defined the mechanism by which PI3Kβ regulates invadopodia. We find that PI3Kβ is specifically activated downstream from integrins, and is required for integrin-stimulated spreading and haptotaxis as well as integrin-stimulated invadopodia formation. Surprisingly, these integrin-stimulated and PI3Kβ-dependent responses require the production of PI(3,4)P(2) by the phosphoinositide 5′-phosphatase SHIP2. Thus, integrin activation of PI3Kβ is coupled to the SHIP2-dependent production of PI(3,4)P(2,) which regulates the recruitment of PH domain-containing scaffolds such as lamellipodin to invadopodia. These findings provide novel mechanistic insight into the role of PI3Kβ in the regulation of invadopodia in breast cancer cells.
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spelling pubmed-67410642019-10-30 PI3Kβ links integrin activation and PI(3,4)P(2) production during invadopodial maturation Erami, Zahra Heitz, Samantha Bresnick, Anne R. Backer, Jonathan M. Mol Biol Cell Articles The invasion of tumor cells from the primary tumor is mediated by invadopodia, actin-rich protrusive organelles that secrete matrix metalloproteases and degrade the extracellular matrix. This coupling between protrusive activity and matrix degradation facilitates tumor invasion. We previously reported that the PI3Kβ isoform of PI 3-kinase, which is regulated by both receptor tyrosine kinases and G protein–coupled receptors, is required for invasion and gelatin degradation in breast cancer cells. We have now defined the mechanism by which PI3Kβ regulates invadopodia. We find that PI3Kβ is specifically activated downstream from integrins, and is required for integrin-stimulated spreading and haptotaxis as well as integrin-stimulated invadopodia formation. Surprisingly, these integrin-stimulated and PI3Kβ-dependent responses require the production of PI(3,4)P(2) by the phosphoinositide 5′-phosphatase SHIP2. Thus, integrin activation of PI3Kβ is coupled to the SHIP2-dependent production of PI(3,4)P(2,) which regulates the recruitment of PH domain-containing scaffolds such as lamellipodin to invadopodia. These findings provide novel mechanistic insight into the role of PI3Kβ in the regulation of invadopodia in breast cancer cells. The American Society for Cell Biology 2019-08-15 /pmc/articles/PMC6741064/ /pubmed/31318314 http://dx.doi.org/10.1091/mbc.E19-03-0182 Text en © 2019 Erami et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 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.
spellingShingle Articles
Erami, Zahra
Heitz, Samantha
Bresnick, Anne R.
Backer, Jonathan M.
PI3Kβ links integrin activation and PI(3,4)P(2) production during invadopodial maturation
title PI3Kβ links integrin activation and PI(3,4)P(2) production during invadopodial maturation
title_full PI3Kβ links integrin activation and PI(3,4)P(2) production during invadopodial maturation
title_fullStr PI3Kβ links integrin activation and PI(3,4)P(2) production during invadopodial maturation
title_full_unstemmed PI3Kβ links integrin activation and PI(3,4)P(2) production during invadopodial maturation
title_short PI3Kβ links integrin activation and PI(3,4)P(2) production during invadopodial maturation
title_sort pi3kβ links integrin activation and pi(3,4)p(2) production during invadopodial maturation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741064/
https://www.ncbi.nlm.nih.gov/pubmed/31318314
http://dx.doi.org/10.1091/mbc.E19-03-0182
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