Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 30 November 2001:
Vol. 294. no. 5548, pp. 1881 - 1885
DOI: 10.1126/science.1065763
Prev | Table of Contents | Next

Review

Location, Location, Location: Membrane Targeting Directed by PX Domains

Trey K. Sato,1 Michael Overduin,2 Scott D. Emr1*

Phosphoinositide (PI)-binding domains play critical roles in the intracellular localization of a variety of cell-signaling proteins. The 120-amino acid Phox homology (PX) domain targets proteins to organelle membranes through interactions between two conserved basic motifs within the PX domain and specific PIs. The combination of protein-lipid and protein-protein interactions ensures the proper localization and regulation of PX domain-containing proteins. Upon proper localization, PX domain-containing proteins can then bind to additional proteins and execute their functions in a diverse set of biological pathways, including intracellular protein transport, cell growth and survival, cytoskeletal organization, and neutrophil defense.

With 30,000 to 40,000 genes potentially expressed in the human genome, cells face the difficult task of assembling these gene products into functional complexes and localizing them to appropriate sites. Of course, cells have developed a number of different strategies to deal with this problem, one of which is to spatially restrict proteins to their site of function and thus improve the probability that they will interact with their proper partners. In particular, the targeting of proteins to specific membrane-bound organelles has proven to be an effective cellular mechanism in maintaining the fidelity and efficiency of protein activities. Research within the past decade has identified protein domains that specifically bind the phosphatidylinositol (Ptd-Ins) phospholipids, collectively called phosphoinositides (PIs), as major determinants in localizing proteins to their site of function (1, 2). These PI-binding motifs, which include the C2 (PKC conserved region 2), PH (Pleckstrin homology), FYVE (Fab1p/YOTP/Vac1p/EEA1), ENTH (Epsin NH2-terminal homology) and tubby domains, are found in proteins implicated in a diverse array of cellular processes, such as protein transport, exocytosis, endocytosis, actin cytoskeletal organization, cell growth regulation, and control of gene expression. Through the regulated synthesis of distinct PIs on specific organelles, proteins containing these lipid-binding domains can be targeted and activated at the appropriate site of function. The importance of membrane targeting by PIs is exemplified by a number of human diseases linked to defects in PI signaling (3-5), including cancer, immunodeficiency disorders (X-linked agammaglobulinemina and chronic granulomatous disease), myotubular myopathy, kidney and neurological diseases (oculocerebro-renal syndrome of Lowe), and faciogenital dysplasia (Aarskog-Scott syndrome).

Even with the large number of PI-binding proteins previously identified, genetic and biochemical studies suggest the existence of additional effector molecules. For example, it has long been known that PI synthesis is necessary for the generation of superoxides by the human NADPH oxidase complex, though the connection between these processes had been elusive. Recently, it was determined that Phox Homology (PX) domains, including those in two NADPH oxidase subunits, bind to PIs, identifying another family of effector proteins [(6-11); reviewed in (12)]. Many members of this effector family contain additional motifs that mediate protein-protein interactions and other biochemical activities, such as protein phosphorylation and lipid modification (13). As with other lipid-binding motifs, PX domains play important roles in ensuring that proteins reach their appropriate intracellular location through the binding of membrane-restricted PIs.

1 Department of Cellular and Molecular Medicine and Howard Hughes Medical Institute, University of California at San Diego School of Medicine, La Jolla, CA 92093-0668, USA.
2 Department of Pharmacology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
*   To whom correspondence should be addressed. E-mail: semr{at}ucsd.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Cytosolic Phospholipase A2{alpha} Is Targeted to the p47phox-PX Domain of the Assembled NADPH Oxidase via a Novel Binding Site in Its C2 Domain.
Z. Shmelzer, M. Karter, M. Eisenstein, T. L. Leto, N. Hadad, D. Ben-Menahem, D. Gitler, S. Banani, B. Wolach, M. Rotem, et al. (2008)
J. Biol. Chem. 283, 31898-31908
   Abstract »    Full Text »    PDF »
Platelet-Activating Factor-Mediated Endosome Formation Causes Membrane Translocation of p67phox and p40phox That Requires Recruitment and Activation of p38 MAPK, Rab5a, and Phosphatidylinositol 3-Kinase in Human Neutrophils.
N. J. D. McLaughlin, A. Banerjee, S. Y. Khan, J. L. Lieber, M. R. Kelher, F. Gamboni-Robertson, F. R. Sheppard, E. E. Moore, G. W. Mierau, D. J. Elzi, et al. (2008)
J. Immunol. 180, 8192-8203
   Abstract »    Full Text »    PDF »
Characterization of a Mutation in the Phox Homology Domain of the NADPH Oxidase Component p40phox Identifies A Mechanism for Negative Regulation of Superoxide Production.
J. Chen, R. He, R. D. Minshall, M. C. Dinauer, and R. D. Ye (2007)
J. Biol. Chem. 282, 30273-30284
   Abstract »    Full Text »    PDF »
PX-RICS, a novel splicing variant of RICS, is a main isoform expressed during neural development.
T. Hayashi, T. Okabe, Y. Nasu-Nishimura, F. Sakaue, S. Ohwada, K. Matsuura, T. Akiyama, and T. Nakamura (2007)
Genes Cells 12, 929-939
   Abstract »    Full Text »    PDF »
Suppression of Arabidopsis vesicle-SNARE expression inhibited fusion of H2O2-containing vesicles with tonoplast and increased salt tolerance.
Y. Leshem, N. Melamed-Book, O. Cagnac, G. Ronen, Y. Nishri, M. Solomon, G. Cohen, and A. Levine (2006)
PNAS 103, 18008-18013
   Abstract »    Full Text »    PDF »
Role of the Phox Homology Domain and Phosphorylation in Activation of Serum and Glucocorticoid-regulated Kinase-3.
M. Tessier and J. R. Woodgett (2006)
J. Biol. Chem. 281, 23978-23989
   Abstract »    Full Text »    PDF »
Function of the MAPK scaffold protein, Ste5, requires a cryptic PH domain.
L. S. Garrenton, S. L. Young, and J. Thorner (2006)
Genes & Dev. 20, 1946-1958
   Abstract »    Full Text »    PDF »
Characterization of the megakaryocyte demarcation membrane system and its role in thrombopoiesis.
H. Schulze, M. Korpal, J. Hurov, S.-W. Kim, J. Zhang, L. C. Cantley, T. Graf, and R. A. Shivdasani (2006)
Blood 107, 3868-3875
   Abstract »    Full Text »    PDF »
PtdIns(3)P accumulation in triple lipid-phosphatase-deletion mutants triggers lethal hyperactivation of the Rho1p/Pkc1p cell-integrity MAP kinase pathway.
W. R. Parrish, C. J. Stefan, and S. D. Emr (2005)
J. Cell Sci. 118, 5589-5601
   Abstract »    Full Text »    PDF »
The Phosphoinositide-3-phosphatase MTMR2 Associates with MTMR13, a Membrane-associated Pseudophosphatase Also Mutated in Type 4B Charcot-Marie-Tooth Disease.
F. L. Robinson and J. E. Dixon (2005)
J. Biol. Chem. 280, 31699-31707
   Abstract »    Full Text »    PDF »
Inositol-lipid binding motifs: signal integrators through protein-lipid and protein-protein interactions.
T. Balla (2005)
J. Cell Sci. 118, 2093-2104
   Abstract »    Full Text »    PDF »
Determinants of the Endosomal Localization of Sorting Nexin 1.
Q. Zhong, M. J. Watson, C. S. Lazar, A. M. Hounslow, J. P. Waltho, and G. N. Gill (2005)
Mol. Biol. Cell 16, 2049-2057
   Abstract »    Full Text »    PDF »
The Src Substrate Tks5, Podosomes (Invadopodia), and Cancer Cell Invasion.
S.A. COURTNEIDGE, E.F. AZUCENA JR., I. PASS, D.F. SEALS, and L. TESFAY (2005)
Cold Spring Harb Symp Quant Biol 70, 167-171
   Abstract »    PDF »
Sorting nexin 5 is localized to a subdomain of the early endosomes and is recruited to the plasma membrane following EGF stimulation.
A. Merino-Trigo, M. C. Kerr, F. Houghton, A. Lindberg, C. Mitchell, R. D. Teasdale, and P. A. Gleeson (2004)
J. Cell Sci. 117, 6413-6424
   Abstract »    Full Text »    PDF »
Ligation of lymphocyte function-associated antigen-1 on monocytes decreases very late antigen-4-mediated adhesion through a reactive oxygen species-dependent pathway.
K.-P. Chuang, Y.-F. Huang, Y.-L. Hsu, H.-S. Liu, H.-C. Chen, and C.-C. Shieh (2004)
Blood 104, 4046-4053
   Abstract »    Full Text »    PDF »
Essential Role for the Myotubularin-related Phosphatase Ymr1p and the Synaptojanin-like Phosphatases Sjl2p and Sjl3p in Regulation of Phosphatidylinositol 3-Phosphate in Yeast.
W. R. Parrish, C. J. Stefan, and S. D. Emr (2004)
Mol. Biol. Cell 15, 3567-3579
   Abstract »    Full Text »    PDF »
Structural Basis of Membrane Targeting by the Phox Homology Domain of Cytokine-independent Survival Kinase (CISK-PX).
Y. Xing, D. Liu, R. Zhang, A. Joachimiak, Z. Songyang, and W. Xu (2004)
J. Biol. Chem. 279, 30662-30669
   Abstract »    Full Text »    PDF »
Phosphoinositides in Constitutive Membrane Traffic.
M. G. Roth (2004)
Physiol Rev 84, 699-730
   Abstract »    Full Text »    PDF »
Late Assembly Motifs of Human T-Cell Leukemia Virus Type 1 and Their Relative Roles in Particle Release.
G. Heidecker, P. A. Lloyd, K. Fox, K. Nagashima, and D. Derse (2004)
J. Virol. 78, 6636-6648
   Abstract »    Full Text »    PDF »
A molecular mechanism for autoinhibition of the tandem SH3 domains of p47phox, the regulatory subunit of the phagocyte NADPH oxidase.
S. Yuzawa, N. N. Suzuki, Y. Fujioka, K. Ogura, H. Sumimoto, and F. Inagaki (2004)
Genes Cells 9, 443-456
   Abstract »    Full Text »    PDF »
HIP1 and HIP1r Stabilize Receptor Tyrosine Kinases and Bind 3-Phosphoinositides via Epsin N-terminal Homology Domains.
T. S. Hyun, D. S. Rao, D. Saint-Dic, L. E. Michael, P. D. Kumar, S. V. Bradley, I. F. Mizukami, K. I. Oravecz-Wilson, and T. S. Ross (2004)
J. Biol. Chem. 279, 14294-14306
   Abstract »    Full Text »    PDF »
NOXO1, Regulation of Lipid Binding, Localization, and Activation of Nox1 by the Phox Homology (PX) Domain.
G. Cheng and J. D. Lambeth (2004)
J. Biol. Chem. 279, 4737-4742
   Abstract »    Full Text »    PDF »
The uniformity of phagosome maturation in macrophages.
R. M. Henry, A. D. Hoppe, N. Joshi, and J. A. Swanson (2004)
J. Cell Biol. 164, 185-194
   Abstract »    Full Text »    PDF »
Sorting Nexin 9 Participates in Clathrin-mediated Endocytosis through Interactions with the Core Components.
R. Lundmark and S. R. Carlsson (2003)
J. Biol. Chem. 278, 46772-46781
   Abstract »    Full Text »    PDF »
The DEP Domain Determines Subcellular Targeting of the GTPase Activating Protein RGS9 In Vivo.
K. A. Martemyanov, P. V. Lishko, N. Calero, G. Keresztes, M. Sokolov, K. J. Strissel, I. B. Leskov, J. A. Hopp, A. V. Kolesnikov, C.-K. Chen, et al. (2003)
J. Neurosci. 23, 10175-10181
   Abstract »    Full Text »    PDF »
Golgi Localization of Carbohydrate Sulfotransferases Is a Determinant of L-selectin Ligand Biosynthesis.
C. L. de Graffenried and C. R. Bertozzi (2003)
J. Biol. Chem. 278, 40282-40295
   Abstract »    Full Text »    PDF »
Interaction of Calmodulin, a Sorting Nexin and Kinase-Associated Protein Phosphatase with the Brassica oleracea S Locus Receptor Kinase.
V. Vanoosthuyse, G. Tichtinsky, C. Dumas, T. Gaude, and J. M. Cock (2003)
Plant Physiology 133, 919-929
   Abstract »    Full Text »    PDF »
PI3P signaling regulates receptor sorting but not transport in the endosomal pathway.
A. Petiot, J. Faure, H. Stenmark, and J. Gruenberg (2003)
J. Cell Biol. 162, 971-979
   Abstract »    Full Text »    PDF »
Genetic Analysis of the Myotubularin Family of Phosphatases in Caenorhabditis elegans.
Y. Xue, H. Fares, B. Grant, Z. Li, A. M. Rose, S. G. Clark, and E. Y. Skolnik (2003)
J. Biol. Chem. 278, 34380-34386
   Abstract »    Full Text »    PDF »
Unique targeting of cytosolic phospholipase A2 to plasma membranes mediated by the NADPH oxidase in phagocytes.
Z. Shmelzer, N. Haddad, E. Admon, I. Pessach, T. L. Leto, Z. Eitan-Hazan, M. Hershfinkel, and R. Levy (2003)
J. Cell Biol. 162, 683-692
   Abstract »    Full Text »    PDF »
Reactivation of Formyl Peptide Receptors Triggers the Neutrophil NADPH-oxidase but Not a Transient Rise in Intracellular Calcium.
J. Bylund, A. Bjorstad, D. Granfeldt, A. Karlsson, C. Woschnagg, and C. Dahlgren (2003)
J. Biol. Chem. 278, 30578-30586
   Abstract »    Full Text »    PDF »
Vps27 recruits ESCRT machinery to endosomes during MVB sorting.
D. J. Katzmann, C. J. Stefan, M. Babst, and S. D. Emr (2003)
J. Cell Biol. 162, 413-423
   Abstract »    Full Text »    PDF »
Regulation of phospholipase D1 subcellular cycling through coordination of multiple membrane association motifs.
G. Du, Y. M. Altshuller, N. Vitale, P. Huang, S. Chasserot-Golaz, A. J. Morris, M.-F. Bader, and M. A. Frohman (2003)
J. Cell Biol. 162, 305-315
   Abstract »    Full Text »    PDF »
The Direct Interaction of Phospholipase C-gamma 1 with Phospholipase D2 Is Important for Epidermal Growth Factor Signaling.
I. H. Jang, S. Lee, J. B. Park, J. H. Kim, C. S. Lee, E.-M. Hur, I. S. Kim, K.-T. Kim, H. Yagisawa, P.-G. Suh, et al. (2003)
J. Biol. Chem. 278, 18184-18190
   Abstract »    Full Text »    PDF »
The Adaptor Protein Fish Associates with Members of the ADAMs Family and Localizes to Podosomes of Src-transformed Cells.
C. L. Abram, D. F. Seals, I. Pass, D. Salinsky, L. Maurer, T. M. Roth, and S. A. Courtneidge (2003)
J. Biol. Chem. 278, 16844-16851
   Abstract »    Full Text »    PDF »
Membrane Binding Mechanisms of the PX Domains of NADPH Oxidase p40phox and p47phox.
R. V. Stahelin, A. Burian, K. S. Bruzik, D. Murray, and W. Cho (2003)
J. Biol. Chem. 278, 14469-14479
   Abstract »    Full Text »    PDF »
Two Novel Proteins Activate Superoxide Generation by the NADPH Oxidase NOX1.
B. Banfi, R. A. Clark, K. Steger, and K.-H. Krause (2003)
J. Biol. Chem. 278, 3510-3513
   Abstract »    Full Text »    PDF »
Differential Role of Actin, Clathrin, and Dynamin in Fcgamma Receptor-mediated Endocytosis and Phagocytosis.
S. M. L. Tse, W. Furuya, E. Gold, A. D. Schreiber, K. Sandvig, R. D. Inman, and S. Grinstein (2003)
J. Biol. Chem. 278, 3331-3338
   Abstract »    Full Text »    PDF »
Dual role for phosphoinositides in regulation of yeast and mammalian phospholipase D enzymes.
V. A. Sciorra, S. A. Rudge, J. Wang, S. McLaughlin, J. Engebrecht, and A. J. Morris (2002)
J. Cell Biol. 159, 1039-1049
   Abstract »    Full Text »    PDF »
The Phox Homology (PX) Domain-dependent, 3-Phosphoinositide-mediated Association of Sorting Nexin-1 with an Early Sorting Endosomal Compartment Is Required for Its Ability to Regulate Epidermal Growth Factor Receptor Degradation.
G. E. Cozier, J. Carlton, A. H. McGregor, P. A. Gleeson, R. D. Teasdale, H. Mellor, and P. J. Cullen (2002)
J. Biol. Chem. 277, 48730-48736
   Abstract »    Full Text »    PDF »
Retromer function in endosome-to-Golgi retrograde transport is regulated by the yeast Vps34 PtdIns 3-kinase.
P. Burda, S. M. Padilla, S. Sarkar, and S. D. Emr (2002)
J. Cell Sci. 115, 3889-3900
   Abstract »    Full Text »    PDF »
Novel PtdIns(3)P-binding protein Etf1 functions as an effector of the Vps34 PtdIns 3-kinase in autophagy.
A. E. Wurmser and S. D. Emr (2002)
J. Cell Biol. 158, 761-772
   Abstract »    Full Text »    PDF »
Cooperative Binding of the Cytoplasm to Vacuole Targeting Pathway Proteins, Cvt13 and Cvt20, to Phosphatidylinositol 3-Phosphate at the Pre-autophagosomal Structure Is Required for Selective Autophagy.
D. C. Nice, T. K. Sato, P. E. Stromhaug, S. D. Emr, and D. J. Klionsky (2002)
J. Biol. Chem. 277, 30198-30207
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-kinase regulates {beta}2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/{beta}-arrestin complex.
S. V. Naga Prasad, S. A. Laporte, D. Chamberlain, M. G. Caron, L. Barak, and H. A. Rockman (2002)
J. Cell Biol. 158, 563-575
   Abstract »    Full Text »    PDF »
Regulation of Stress Response Signaling by the N-terminal Dishevelled/EGL-10/Pleckstrin Domain of Sst2, a Regulator of G Protein Signaling in Saccharomyces cerevisiae.
S. A. Burchett, P. Flanary, C. Aston, L. Jiang, K. H. Young, P. Uetz, S. Fields, and H. G. Dohlman (2002)
J. Biol. Chem. 277, 22156-22167
   Abstract »    Full Text »    PDF »
Endosomal localization and function of sorting nexin 1.
Q. Zhong, C. S. Lazar, H. Tronchere, T. Sato, T. Meerloo, M. Yeo, Z. Songyang, S. D. Emr, and G. N. Gill (2002)
PNAS 99, 6767-6772
   Abstract »    Full Text »    PDF »
Protein Lipid Overlay Assay.
S. Dowler, G. Kular, and D. R. Alessi (2002)
Sci. STKE 2002, pl6
   Abstract »    Full Text »    PDF »
A cycle of Vam7p release from and PtdIns 3-P-dependent rebinding to the yeast vacuole is required for homotypic vacuole fusion.
C. Boeddinghaus, A. J. Merz, R. Laage, and C. Ungermann (2002)
J. Cell Biol. 157, 79-90
   Abstract »    Full Text »    PDF »
Discovery of Novel Tumor Markers of Pancreatic Cancer using Global Gene Expression Technology.
C. A. Iacobuzio-Donahue, A. Maitra, G. L. Shen-Ong, T. van Heek, R. Ashfaq, R. Meyer, K. Walter, K. Berg, M. A. Hollingsworth, J. L. Cameron, et al. (2002)
Am. J. Pathol. 160, 1239-1249
   Abstract »    Full Text »    PDF »
G-Protein-coupled Receptor Function in Heart Failure.
S.V. NAGA PRASAD, J. NIENABER, and H.A. ROCKMAN (2002)
Cold Spring Harb Symp Quant Biol 67, 439-444
   Abstract »    PDF »
Regulation of Fab1 Phosphatidylinositol 3-Phosphate 5-Kinase Pathway by Vac7 Protein and Fig4, a Polyphosphoinositide Phosphatase Family Member.
J. D. Gary, T. K. Sato, C. J. Stefan, C. J. Bonangelino, L. S. Weisman, and S. D. Emr (2002)
Mol. Biol. Cell 13, 1238-1251
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)