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Science 314 (5804): 1458-1461

Copyright © 2006 by the American Association for the Advancement of Science

PI(3,4,5)P3 and PI(4,5)P2 Lipids Target Proteins with Polybasic Clusters to the Plasma Membrane

Won Do Heo,1 Takanari Inoue,1 Wei Sun Park,1 Man Lyang Kim,1 Byung Ouk Park,2 Thomas J. Wandless,1 Tobias Meyer1*

Abstract: Many signaling, cytoskeletal, and transport proteins have to be localized to the plasma membrane (PM) in order to carry out their function. We surveyed PM-targeting mechanisms by imaging the subcellular localization of 125 fluorescent protein–conjugated Ras, Rab, Arf, and Rho proteins. Out of 48 proteins that were PM-localized, 37 contained clusters of positively charged amino acids. To test whether these polybasic clusters bind negatively charged phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] lipids, we developed a chemical phosphatase activation method to deplete PM PI(4,5)P2. Unexpectedly, proteins with polybasic clusters dissociated from the PM only when both PI(4,5)P2 and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] were depleted, arguing that both lipid second messengers jointly regulate PM targeting.

1 Department of Molecular Pharmacology, 318 Campus Drive, Clark Building, Stanford University Medical School, Stanford, CA 94305, USA.
2 Division of Applied Life Science (BK21 Program) and Environmental Biotechnology National Core Research Center, Gyeongsang National University, Jinju 660-701, Korea.

* To whom correspondence should be addressed. E-mail: tobias1{at}

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   Abstract »    Full Text »    PDF »
Regulation of PLC{beta}1a membrane anchoring by its substrate phosphatidylinositol (4,5)-bisphosphate.
M. J. W. Adjobo-Hermans, J. Goedhart, and T. W. J. Gadella Jr (2008)
J. Cell Sci. 121, 3770-3777
   Abstract »    Full Text »    PDF »
Acanthamoeba Myosin IC Colocalizes with Phosphatidylinositol 4,5-Bisphosphate at the Plasma Membrane Due to the High Concentration of Negative Charge.
H. Brzeska, K.-J. Hwang, and E. D. Korn (2008)
J. Biol. Chem. 283, 32014-32023
   Abstract »    Full Text »    PDF »
Contribution of Each Membrane Binding Domain of the CTP:Phosphocholine Cytidylyltransferase-{alpha} Dimer to Its Activation, Membrane Binding, and Membrane Cross-bridging.
S. Taneva, M. K. Dennis, Z. Ding, J. L. Smith, and R. B. Cornell (2008)
J. Biol. Chem. 283, 28137-28148
   Abstract »    Full Text »    PDF »
Rac1 accumulates in the nucleus during the G2 phase of the cell cycle and promotes cell division.
D. Michaelson, W. Abidi, D. Guardavaccaro, M. Zhou, I. Ahearn, M. Pagano, and M. R. Philips (2008)
J. Cell Biol. 181, 485-496
   Abstract »    Full Text »    PDF »
Differential Interference of Chlorpromazine with the Membrane Interactions of Oncogenic K-Ras and Its Effects on Cell Growth.
S. Eisenberg, K. Giehl, Y. I. Henis, and M. Ehrlich (2008)
J. Biol. Chem. 283, 27279-27288
   Abstract »    Full Text »    PDF »
Phosphatidylinositol (4,5)-bisphosphate Modulates Nox5 Localization via an N-Terminal Polybasic Region.
T. Kawahara and J. D. Lambeth (2008)
Mol. Biol. Cell 19, 4020-4031
   Abstract »    Full Text »    PDF »
Differential Roles of Phosphatidylserine, PtdIns(4,5)P2, and PtdIns(3,4,5)P3 in Plasma Membrane Targeting of C2 Domains: MOLECULAR DYNAMICS SIMULATION, MEMBRANE BINDING, AND CELL TRANSLOCATION STUDIES OF THE PKC{alpha} C2 Domain.
D. Manna, N. Bhardwaj, M. S. Vora, R. V. Stahelin, H. Lu, and W. Cho (2008)
J. Biol. Chem. 283, 26047-26058
   Abstract »    Full Text »    PDF »
Wnt3a-Mediated Formation of Phosphatidylinositol 4,5-Bisphosphate Regulates LRP6 Phosphorylation.
W. Pan, S.-C. Choi, H. Wang, Y. Qin, L. Volpicelli-Daley, L. Swan, L. Lucast, C. Khoo, X. Zhang, L. Li, et al. (2008)
Science 321, 1350-1353
   Abstract »    Full Text »    PDF »
SopB promotes phosphatidylinositol 3-phosphate formation on Salmonella vacuoles by recruiting Rab5 and Vps34.
G. V. Mallo, M. Espina, A. C. Smith, M. R. Terebiznik, A. Aleman, B. B. Finlay, L. E. Rameh, S. Grinstein, and J. H. Brumell (2008)
J. Cell Biol. 182, 741-752
   Abstract »    Full Text »    PDF »
Pituitary Adenylate Cyclase-Activating Polypeptide 38-Mediated Rin Activation Requires Src and Contributes to the Regulation of Hsp27 Signaling during Neuronal Differentiation.
G.-X. Shi, L. Jin, and D. A. Andres (2008)
Mol. Cell. Biol. 28, 4940-4951
   Abstract »    Full Text »    PDF »
Dissociation of Rac1(GDP){middle dot}RhoGDI Complexes by the Cooperative Action of Anionic Liposomes Containing Phosphatidylinositol 3,4,5-Trisphosphate, Rac Guanine Nucleotide Exchange Factor, and GTP.
Y. Ugolev, Y. Berdichevsky, C. Weinbaum, and E. Pick (2008)
J. Biol. Chem. 283, 22257-22271
   Abstract »    Full Text »    PDF »

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