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Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1

Class I phosphoinositide 3-kinases (PI3Ks) are implicated in many cellular responses controlled by receptor tyrosine kinases (RTKs), including actin cytoskeletal remodeling. Within this pathway, Rac is a key downstream target/effector of PI3K. However, how the signal is routed from PI3K to Rac is un...

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Autores principales: Innocenti, Metello, Frittoli, Emanuela, Ponzanelli, Isabella, Falck, John R., Brachmann, Saskia M., Di Fiore, Pier Paolo, Scita, Giorgio
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172734/
https://www.ncbi.nlm.nih.gov/pubmed/12515821
http://dx.doi.org/10.1083/jcb.200206079
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author Innocenti, Metello
Frittoli, Emanuela
Ponzanelli, Isabella
Falck, John R.
Brachmann, Saskia M.
Di Fiore, Pier Paolo
Scita, Giorgio
author_facet Innocenti, Metello
Frittoli, Emanuela
Ponzanelli, Isabella
Falck, John R.
Brachmann, Saskia M.
Di Fiore, Pier Paolo
Scita, Giorgio
author_sort Innocenti, Metello
collection PubMed
description Class I phosphoinositide 3-kinases (PI3Ks) are implicated in many cellular responses controlled by receptor tyrosine kinases (RTKs), including actin cytoskeletal remodeling. Within this pathway, Rac is a key downstream target/effector of PI3K. However, how the signal is routed from PI3K to Rac is unclear. One possible candidate for this function is the Rac-activating complex Eps8–Abi1–Sos-1, which possesses Rac-specific guanine nucleotide exchange factor (GEF) activity. Here, we show that Abi1 (also known as E3b1) recruits PI3K, via p85, into a multimolecular signaling complex that includes Eps8 and Sos-1. The recruitment of p85 to the Eps8–Abi1–Sos-1 complex and phosphatidylinositol 3, 4, 5 phosphate (PIP3), the catalytic product of PI3K, concur to unmask its Rac-GEF activity in vitro. Moreover, they are indispensable for the activation of Rac and Rac-dependent actin remodeling in vivo. On growth factor stimulation, endogenous p85 and Abi1 consistently colocalize into membrane ruffles, and cells lacking p85 fail to support Abi1-dependent Rac activation. Our results define a mechanism whereby propagation of signals, originating from RTKs or Ras and leading to actin reorganization, is controlled by direct physical interaction between PI3K and a Rac-specific GEF complex.
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spelling pubmed-21727342008-05-01 Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1 Innocenti, Metello Frittoli, Emanuela Ponzanelli, Isabella Falck, John R. Brachmann, Saskia M. Di Fiore, Pier Paolo Scita, Giorgio J Cell Biol Report Class I phosphoinositide 3-kinases (PI3Ks) are implicated in many cellular responses controlled by receptor tyrosine kinases (RTKs), including actin cytoskeletal remodeling. Within this pathway, Rac is a key downstream target/effector of PI3K. However, how the signal is routed from PI3K to Rac is unclear. One possible candidate for this function is the Rac-activating complex Eps8–Abi1–Sos-1, which possesses Rac-specific guanine nucleotide exchange factor (GEF) activity. Here, we show that Abi1 (also known as E3b1) recruits PI3K, via p85, into a multimolecular signaling complex that includes Eps8 and Sos-1. The recruitment of p85 to the Eps8–Abi1–Sos-1 complex and phosphatidylinositol 3, 4, 5 phosphate (PIP3), the catalytic product of PI3K, concur to unmask its Rac-GEF activity in vitro. Moreover, they are indispensable for the activation of Rac and Rac-dependent actin remodeling in vivo. On growth factor stimulation, endogenous p85 and Abi1 consistently colocalize into membrane ruffles, and cells lacking p85 fail to support Abi1-dependent Rac activation. Our results define a mechanism whereby propagation of signals, originating from RTKs or Ras and leading to actin reorganization, is controlled by direct physical interaction between PI3K and a Rac-specific GEF complex. The Rockefeller University Press 2003-01-06 /pmc/articles/PMC2172734/ /pubmed/12515821 http://dx.doi.org/10.1083/jcb.200206079 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Report
Innocenti, Metello
Frittoli, Emanuela
Ponzanelli, Isabella
Falck, John R.
Brachmann, Saskia M.
Di Fiore, Pier Paolo
Scita, Giorgio
Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1
title Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1
title_full Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1
title_fullStr Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1
title_full_unstemmed Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1
title_short Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1
title_sort phosphoinositide 3-kinase activates rac by entering in a complex with eps8, abi1, and sos-1
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172734/
https://www.ncbi.nlm.nih.gov/pubmed/12515821
http://dx.doi.org/10.1083/jcb.200206079
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