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

Metello Innocenti, Emanuela Frittoli, Isabella Ponzanelli, John R. Falck, Saskia M. Brachmann, Pier Paolo Di Fiore, Giorgio Scita

Research output: Contribution to journalArticle

191 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)17-23
Number of pages7
JournalJournal of Cell Biology
Volume160
Issue number1
DOIs
StatePublished - Jan 6 2003

Keywords

  • Actin remodeling
  • GEF
  • PI3K
  • RTK
  • Signaling

ASJC Scopus subject areas

  • Cell Biology

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    Innocenti, M., Frittoli, E., Ponzanelli, I., Falck, J. R., Brachmann, S. M., Di Fiore, P. P., & Scita, G. (2003). Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1. Journal of Cell Biology, 160(1), 17-23. https://doi.org/10.1083/jcb.200206079