Advan. Enzyme Regul. 45 (2005) 171–185 Modification of protein sub-nuclear localization by synthetic phosphoinositides: Evidence for nuclear phosphoinositide signaling mechanisms Or Gozani a, , Seth J. Field b , Colin G. Ferguson c,d , Mark Ewalt a , Christopher Mahlke a , Lewis C. Cantley b , Glenn D. Prestwich c , Junying Yuan a a Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA b Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA c Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA d Echelon Biosciences, Inc. 675 Arapeen Dr., Suite 302, Salt Lake City, UT 84108, USA Introduction Phosphoinositides (PtdInsPs) regulate diverse cellular functions that influence survival, growth, and proliferation, and dysregulated PtdInsP homeostasis is implicated in many disease processes (Cantley, 2002; Maehama et al., 2001; Payrastre et al., 2001). For example, in tumor tissues, the PtdInsP phosphatase gene, PTEN (phosphatase and tensin homologue deleted on chromosome 10; EC 3.1.3.67) is frequently mutated, whereas expression of the PtdInsP kinase, phosphatidylino- sitol 3-kinase (PI3K; EC 2.7.1.153) is often upregulated (Cantley, 2002). Mouse models have also implicated PI3K in the pathogenesis of diabetes and immunode- ficiencies, and mutations in the myotubularin family of PtdInsP phosphatases have been linked to myopathies and neuropathies (Fruman and Cantley, 2002; Mauvais- Jarvis et al., 2002; Taylor et al., 2000). These and many other PtdInsP kinases and phosphatases generate seven different PtdInsP species, which are thought to mediate ARTICLE IN PRESS www.elsevier.com/locate/advenzreg 0065-2571/$ - see front matter r 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.advenzreg.2005.02.010 Corresponding author. E-mail address: ogozani@stanford.edu (O. Gozani).