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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6 January 2003
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January 06 2003
Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1
Metello Innocenti,
Metello Innocenti
1Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
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Emanuela Frittoli,
Emanuela Frittoli
1Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
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Isabella Ponzanelli,
Isabella Ponzanelli
1Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
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John R. Falck,
John R. Falck
2Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Saskia M. Brachmann,
Saskia M. Brachmann
3Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Institute of Medicine, Boston, MA 02115
4Freie Universitaet Berlin, Institut fuer Bohemia, 14195 Berlin, Germany
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Pier Paolo Di Fiore,
Pier Paolo Di Fiore
1Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
5The FIRC Institute for Molecular Oncology (IFOM), 20134 Milan, Italy
6Dipartimento di Medicina Chirurgia ed Odontoiatria, Universitá degli Studi di Milano, 20122 Milano, Italy
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Giorgio Scita
Giorgio Scita
1Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
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Metello Innocenti
1Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
Emanuela Frittoli
1Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
Isabella Ponzanelli
1Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
John R. Falck
2Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390
Saskia M. Brachmann
3Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Institute of Medicine, Boston, MA 02115
4Freie Universitaet Berlin, Institut fuer Bohemia, 14195 Berlin, Germany
Pier Paolo Di Fiore
1Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
5The FIRC Institute for Molecular Oncology (IFOM), 20134 Milan, Italy
6Dipartimento di Medicina Chirurgia ed Odontoiatria, Universitá degli Studi di Milano, 20122 Milano, Italy
Giorgio Scita
1Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
Address correspondence to Giorgio Scita, Dept. of Experimental Oncology, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy. Tel.: 39-0257489825. Fax: 39-0257489851. E-mail: [email protected]
The online version of this article contains supplemental material.
*
Abbreviations used in this paper: DH, Dbl homology; GEF, guanine nucleotide exchange factor; MEF, mouse embryonic fibroblast; PH, pleckstrin homology; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol 3, 4, 5 phosphate; RTK, receptor tyrosine kinase.
Received:
June 17 2002
Revision Received:
October 22 2002
Accepted:
November 26 2002
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 160 (1): 17–23.
Article history
Received:
June 17 2002
Revision Received:
October 22 2002
Accepted:
November 26 2002
Citation
Metello Innocenti, Emanuela Frittoli, Isabella Ponzanelli, John R. Falck, Saskia M. Brachmann, Pier Paolo Di Fiore, Giorgio Scita; Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1 . J Cell Biol 6 January 2003; 160 (1): 17–23. doi: https://doi.org/10.1083/jcb.200206079
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