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

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.

c-Cbl-facilitated cytoskeletal effects in v-Abl-transformed fibroblasts are regulated by membrane association of c-Cbl

“…Tyrosine phosphorylation of c-Cbl and interaction of c-Cbl with PI3K are indispensable for c-Cbl-dependent signaling that leads to cytoskeletal effects in v-Abl-3T3 fibroblasts (Feshchenko et al, 1999;Teckchandani et al, 2001Teckchandani et al, , 2005b. Furthermore, functions of PI3K and several proteins that may act downstream of c-Cbl in this system have been shown to require their membrane localization (Abassi and Vuori, 2002;Innocenti et al, 2003;Arthur et al, 2004). Together, these findings suggested that tyrosine phosphorylation of c-Cbl may play a role in mediating its membrane SLAP enhances c-Cbl-mediated cell spreading and adhesion G Swaminathan et al localization in v-Abl-3T3 cells.…”

Evidence That Phosphatidylinositol 3-Kinase- and Mitogen-activated Protein Kinase Kinase-4/c-Jun NH2-terminal Kinase-dependent Pathways Cooperate to Maintain Lung Cancer Cell Survival

“…Although we have yet to identify the mechanism by which ⌬p85 inhibits Rac-1, cell type-specific factors may be important. Recent findings indicate that p85 activates Rac-1 by associating with a multiprotein complex (including Eps8, Abi1, and SOS-1) that binds to p85 SH2 domains (38). We hypothesize that, in certain cell types, the p85 inter-SH2 domain is also required for Rac-1 activation.…”

“…p85␣ associates with Rac-1, an upstream activator of JNK, and activates Rac-1 through association with a multiprotein complex that binds to p85 SH2 domains (38). We investi- Ad5-CMV or treated with medium alone (Ϫ).…”

Anti-migratory and Anti-invasive Effect of Somatostatin in Human Neuroblastoma Cells

“…We found that somatostatin does not directly affect PI3-K activity, but potently interferes with the Rac activation induced by PDGF, thus suggesting that it acts on the pathway between PI3-K and Rac. This pathway has been recently investigated (but not totally clarified) and implies the involvement of Rac-specific guanine nucleotide exchange factors such as Vav, Tiam-1, and Sos-1, which generally form multi-molecular complexes with other proteins (32,33,34). Future studies are necessary to identify the molecular target of somatostatin along this route.…”