PMID- 17565979 OWN - NLM STAT- MEDLINE DCOM- 20070919 LR - 20211203 IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 282 IP - 32 DP - 2007 Aug 10 TI - P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration. PG - 23708-15 AB - Polarized cell migration results from the transduction of extra-cellular cues promoting the activation of Rho GTPases with the intervention of multidomain proteins, including guanine exchange factors. P-Rex1 and P-Rex2 are Rac GEFs connecting Gbetagamma and phosphatidylinositol 3-kinase signaling to Rac activation. Their complex architecture suggests their regulation by protein-protein interactions. Novel mechanisms of activation of Rho GTPases are associated with mammalian target of rapamycin (mTOR), a serine/threonine kinase known as a central regulator of cell growth and proliferation. Recently, two independent multiprotein complexes containing mTOR have been described. mTORC1 links to the classical rapamycin-sensitive pathways relevant for protein synthesis; mTORC2 links to the activation of Rho GTPases and cytoskeletal events via undefined mechanisms. Here we demonstrate that P-Rex1 and P-Rex2 establish, through their tandem DEP domains, interactions with mTOR, suggesting their potential as effectors in the signaling of mTOR to Rac activation and cell migration. This possibility was consistent with the effect of dominant-negative constructs and short hairpin RNA-mediated knockdown of P-Rex1, which decreased mTOR-dependent leucine-induced activation of Rac and cell migration. Rapamycin, a widely used inhibitor of mTOR signaling, did not inhibit Rac activity and cell migration induced by leucine, indicating that P-Rex1, which we found associated to both mTOR complexes, is only active when in the mTORC2 complex. mTORC2 has been described as the catalytic complex that phosphorylates AKT/PKB at Ser-473 and elicits activation of Rho GTPases and cytoskeletal reorganization. Thus, P-Rex1 links mTOR signaling to Rac activation and cell migration. FAU - Hernandez-Negrete, Ivette AU - Hernandez-Negrete I AD - Department of Pharmacology, CINVESTAV-IPN, Apartado Postal 14-740, Mexico DF, 07000 Mexico. FAU - Carretero-Ortega, Jorge AU - Carretero-Ortega J FAU - Rosenfeldt, Hans AU - Rosenfeldt H FAU - Hernandez-Garcia, Ricardo AU - Hernandez-Garcia R FAU - Calderon-Salinas, J Victor AU - Calderon-Salinas JV FAU - Reyes-Cruz, Guadalupe AU - Reyes-Cruz G FAU - Gutkind, J Silvio AU - Gutkind JS FAU - Vazquez-Prado, Jose AU - Vazquez-Prado J LA - eng GR - R01TW006664/TW/FIC NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20070612 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Guanine Nucleotide Exchange Factors) RN - 0 (PREX1 protein, human) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.6.5.2 (rac GTP-Binding Proteins) RN - EC 3.6.5.2 (rho GTP-Binding Proteins) RN - GMW67QNF9C (Leucine) SB - IM MH - Cell Line MH - Cell Movement MH - Cell Proliferation MH - Guanine Nucleotide Exchange Factors/metabolism/*physiology MH - HeLa Cells MH - Humans MH - Leucine/chemistry MH - Models, Biological MH - Protein Biosynthesis MH - Protein Kinases/*metabolism MH - Signal Transduction MH - TOR Serine-Threonine Kinases MH - Two-Hybrid System Techniques MH - rac GTP-Binding Proteins/*metabolism MH - rho GTP-Binding Proteins/metabolism EDAT- 2007/06/15 09:00 MHDA- 2007/09/20 09:00 CRDT- 2007/06/15 09:00 PHST- 2007/06/15 09:00 [pubmed] PHST- 2007/09/20 09:00 [medline] PHST- 2007/06/15 09:00 [entrez] AID - S0021-9258(20)54586-9 [pii] AID - 10.1074/jbc.M703771200 [doi] PST - ppublish SO - J Biol Chem. 2007 Aug 10;282(32):23708-15. doi: 10.1074/jbc.M703771200. Epub 2007 Jun 12.