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

doi:10.1083/jcb.200206079

Published 6 January 2003. doi:10.1083/jcb.200206079

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

Metello Innocenti¹, Emanuela Frittoli¹, Isabella Ponzanelli¹, John R. Falck², Saskia M. Brachmann³^,4, Pier Paolo Di Fiore¹^,5^,6 and Giorgio Scita¹

¹ Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
² Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390
³ Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Institute of Medicine, Boston, MA 02115
⁴ Freie Universitaet Berlin, Institut fuer Bohemia, 14195 Berlin, Germany
⁵ The FIRC Institute for Molecular Oncology (IFOM), 20134 Milan, Italy
⁶ Dipartimento di Medicina Chirurgia ed Odontoiatria, Universitá degli Studi di Milano, 20122 Milano, 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: gscita{at}ieo.it

Class I phosphoinositide 3-kinases (PI3Ks) are implicated inmany cellular responses controlled by receptor tyrosine kinases(RTKs), including actin cytoskeletal remodeling. Within thispathway, Rac is a key downstream target/effector of PI3K. However,how the signal is routed from PI3K to Rac is unclear. One possiblecandidate 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 complexthat includes Eps8 and Sos-1. The recruitment of p85 to theEps8–Abi1–Sos-1 complex and phosphatidylinositol3, 4, 5 phosphate (PIP3), the catalytic product of PI3K, concurto unmask its Rac-GEF activity in vitro. Moreover, they areindispensable for the activation of Rac and Rac-dependent actinremodeling in vivo. On growth factor stimulation, endogenousp85 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 anda Rac-specific GEF complex.

Key Words: PI3K; RTK; actin remodeling; signaling; GEF

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