Structure and Function of the PB1 Domain, a Protein Interaction Module Conserved in Animals, Fungi, Amoebas, and Plants
Abstract
Proteins containing the PB1 domain, a protein interaction module conserved in animals, fungi, amoebas, and plants, participate in diverse biological processes. The PB1 domains adopt a ubiquitin-like β-grasp fold, containing two α helices and a mixed five-stranded β sheet, and are classified into groups harboring an acidic OPCA motif (type I), the invariant lysine residue on the first β strand (type II), or both (type I/II). The OPCA motif of a type I PB1 domain forms salt bridges with basic residues, especially the conserved lysine, of a type II PB1 domain, thereby mediating a specific PB1-PB1 heterodimerization, whereas additional contacts contribute to high affinity and specificity of the modular interaction. The canonical PB1 dimerization is required for the formation of complexes between p40phox and p67phox (for activation of the NADPH oxidase crucial for mammalian host defense), between the scaffold Bem1 and the guanine nucleotide exchange factor Cdc24 (for polarity establishment in yeasts), and between the polarity protein Par6 and atypical protein kinase C (for cell polarization in animal cells), as well as for the interaction between the mitogen-activated protein kinase kinase kinases MEKK2 or MEKK3 and the downstream target mitogen-activated protein kinase kinase MEK5 (for early cardiovascular development in mammals). PB1 domains can also mediate interactions with other protein domains. For example, an intramolecular interaction between the PB1 and PX domains of p40phox regulates phagosomal targeting of the microbicidal NADPH oxidase; the PB1 domain of MEK5 is likely responsible for binding to the downstream kinase ERK5, which lacks a PB1 domain; and the scaffold protein Nbr1 associates through a PB1-containing region with titin, a sarcomere protein without a PB1 domain. This Review describes various aspects of PB1 domains at the molecular and cellular levels.
Abstract
With 9 figures, four interactive structure figures, and 170 citations, this Review describes the structure-function relationships of proteins with PB1 domains. Three types of PB1-containing proteins occur: those with a type I domain, those with a type II domain, and those with both type I and type II (type I/II). The type I domain mediates interactions with proteins containing a type II domain in a canonical PB1-PB1 interaction. Interactions mediated by PB1 domains are important for organizing cell structure, for example, in polarized cells (epithelial cells and neurons) and in skeletal muscle. In addition, interactions involving PB1 domains influence the activation of mitogen-activated protein kinase signaling and activation of NADPH oxidase.
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References
1.
T. Pawson, P. Nash, Assembly of cell regulatory systems through protein interaction domains. Science 300, 445–452 (2003).
2.
T. Pawson, M. Raina, P. Nash, Interaction domains: From simple binding events to complex cellular behavior. FEBS Lett. 513, 2–10 (2002).
3.
T. Ito, Y. Matsui, T. Ago, K. Ota, H. Sumimoto, Novel modular domain PB1 recognizes PC motif to mediate functional protein-protein interactions. EMBO J. 20, 3938–3946 (2001).
4.
C. P. Ponting, T. Ito, J. Moscat, M. T. Diaz-Meco, F. Inagaki, H. Sumimoto, OPR, PC and AID: All in the PB1 family. Trends Biochem. Sci. 27, 10 (2002).
5.
Y. Noda, M. Kohjima, T. Izaki, K. Ota, S. Yoshinaga, F. Inagaki, T. Ito, H. Sumimoto, Molecular recognition in dimerization between PB1 domains. J. Biol. Chem. 278, 43516–43524 (2003).
6.
J. Moscat, M. T. Diaz-Meco, A. Albert, S. Campuzano, Cell signaling and function organized by PB1 domain interactions. Mol. Cell 23, 631–640 (2006).
7.
H. Terasawa, Y. Noda, T. Ito, H. Hatanaka, S. Ichikawa, K. Ogura, H. Sumimoto, F. Inagaki, Structure and ligand recognition of the PB1 domain: A novel protein module binding to the PC motif. EMBO J. 20, 3947–3956 (2001).
8.
M. I. Wilson, D. J. Gill, O. Perisic, M. T. Quinn, R. L. Williams, PB1 domain-mediated heterodimerization in NADPH oxidase and signaling complexes of atypical protein kinase C with Par6 and p62. Mol. Cell 12, 39–50 (2003).
9.
T. Lamark, M. Perander, H. Outzen, K. Kristiansen, A. Øvervatn, E. Michaelsen, G. Bjørkøy, T. Johansen, Interaction codes within the family of mammalian Phox and Bem1p domain-containing proteins. J. Biol. Chem. 278, 34568–34581 (2003).
10.
S. Yoshinaga, M. Kohjima, K. Ogura, M. Yokochi, R. Takeya, T. Ito, H. Sumimoto, F. Inagaki, The PB1 domain and the PC motif-containing region are structurally similar protein binding modules. EMBO J. 22, 4888–4897 (2003).
11.
Y. Hirano, S. Yoshinaga, K. Ogura, M. Yokochi, Y. Noda, H. Sumimoto, F. Inagaki, Solution structure of atypical protein kinase C PB1 domain and its mode of interaction with ZIP/p62 and MEK5. J. Biol. Chem. 279, 31883–31890 (2004).
12.
J. Chenevert, K. Corrado, A. Bender, J. Pringle, I. Herskowitz, A yeast gene (BEM1) necessary for cell polarization whose product contains two SH3 domains. Nature 356, 77–79 (1992).
13.
J. Chenevert, N. Valtz, I. Herskowitz, Identification of genes required for normal pheromone-induced cell polarization in Saccharomyces cerevisiae. Genetics 136, 1287–1296 (1994).
14.
A. Bender, J. R. Pringle, Use of a screen for synthetic lethal and multicopy suppressee mutants to identify two new genes involved in morphogenesis in Saccharomyces cerevisiae. Mol. Cell. Biol. 11, 1295–1305 (1991).
15.
J. Peterson, Y. Zheng, L. Bender, A. Myers, R. Cerione, A. Bender, Interactions between the bud emergence proteins Bem1p and Bem2p and Rho-type GTPases in yeast. J. Cell Biol. 127, 1395–1406 (1994).
16.
J. D. Lambeth, NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 4, 181–189 (2004).
17.
M. Geiszt, T. L. Leto, The Nox family of NAD(P)H oxidases: Host defense and beyond. J. Biol. Chem. 279, 51715–51718 (2004).
18.
H. Sumimoto, K. Miyano, R. Takeya, Molecular composition and regulation of the Nox family NAD(P)H oxidases. Biochem. Biophys. Res. Commun. 338, 677–686 (2005).
19.
A. R. Cross, A. W. Segal, The NADPH oxidase of professional phagocytes—prototype of the NOX electron transport chain systems. Biochim. Biophys. Acta 1657, 1–22 (2004).
20.
W. M. Nauseef, Assembly of the phagocyte NADPH oxidase. Histochem. Cell Biol. 122, 277–291 (2004).
21.
M. T. Quinn, K. A. Gauss, Structure and regulation of the neutrophil respiratory burst oxidase: Comparison with nonphagocyte oxidases. J. Leukoc. Biol. 76, 760–781 (2004).
22.
R. Nakamura, H. Sumimoto, K. Mizuki, K. Hata, T. Ago, S. Kitajima, K. Takeshige, Y. Sakaki, T. Ito, The PC motif: A novel and evolutionarily conserved sequence involved in interaction between p40phox and p67phox, SH3 domain-containing cytosolic factors of the phagocyte NADPH oxidase. Eur. J. Biochem. 251, 583–589 (1998).
23.
H. Sumimoto, T. Ito, K. Hata, K. Mizuki, R. Nakamura, Y. Kage, Y. Sakaki, M. Nakamura, K. Takeshige, Membrane translocation of cytosolic factors in activation of the phagocyte NADPH oxidase: Role of protein-protein interaction. In Membrane Proteins: Structure, Function and Expression Control, N. Hamasaki, K. Mihara, Eds. (Kyushu Univ. Press, Fukuoka, Japan, 1997), pp. 235–245.
24.
E. C. Chang, M. Barr, Y. Wang, V. Jung, H. P. Xu, M. H. Wigler, Cooperative interaction of S. pombe proteins required for mating and morphogenesis. Cell 79, 131–141 (1994).
25.
G. Zhou, Z. Q. Bao, J. E. Dixon, Components of a new human protein kinase signal transduction pathway. J. Biol. Chem. 270, 12665–12669 (1995).
26.
C. P. Ponting, Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3-kinases: Binding partners of SH3 domains? Protein Sci. 5, 2353–2357 (1996).
27.
J. Moscat, M. T. Diaz-Meco, The atypical protein kinase Cs. Functional specificity mediated by specific protein adapters. EMBO Rep. 1, 399–403 (2000).
28.
H. Koga, H. Terasawa, H. Nunoi, K. Takeshige, F. Inagaki, H. Sumimoto, Tetratricopeptide repeat (TPR) motifs of p67phox participate in interaction with the small GTPase Rac and activation of the phagocyte NADPH oxidase. J. Biol. Chem. 274, 25051–25060 (1999).
29.
K. Lapouge, S. J. Smith, P. A. Walker, S. J. Gamblin, S. J. Smerdon, K. Rittinger, Structure of the TPR domain of p67phox in complex with Rac GTP. Mol. Cell 6, 899–907 (2000).
30.
Y. Yamaguchi, K. Ota, T. Ito, A novel Cdc42-interacting domain of the yeast polarity establishment protein Bem1. Implications for modulation of mating pheromone signaling. J. Biol. Chem. 282, 29–38 (2007).
31.
G. Joberty, C. Petersen, L. Gao, I. G. Macara, The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat. Cell Biol. 2, 531–539 (2000).
32.
D. Lin, A. S. Edwards, J. P. Fawcett, G. Mbamalu, J. D. Scott, T. Pawson, A mammalian PAR-3-PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nat. Cell Biol. 2, 540–547 (2000).
33.
T. Yamanaka, Y. Horikoshi, A. Suzuki, Y. Sugiyama, K. Kitamura, R. Maniwa, Y. Nagai, A. Yamashita, T. Hirose, H. Ishikawa, S. Ohno, PAR-6 regulates aPKC activity in a novel way and mediates cell-cell contact-induced formation of the epithelial junctional complex. Genes Cells 6, 721–731 (2001).
34.
Y. Noda, R. Takeya, S. Ohno, S. Naito, T. Ito, H. Sumimoto, Human homologues of the Caenorhabditis elegans cell polarity protein PAR6 as an adaptor that links the small GTPases Rac and Cdc42 to atypical protein kinase C. Genes Cells 6, 107–119 (2001).
35.
S. M. Garrard, C. T. Capaldo, L. Gao, M. K. Rosen, I. G. Macara, D. R. Tomchick, Structure of Cdc42 in a complex with the GTPase-binding domain of the cell polarity protein, Par6. EMBO J. 22, 1125–1133 (2003).
36.
Y. Hirano, S. Yoshinaga, R. Takeya, N. N. Suzuki, M. Horiuchi, M. Kohjima, H. Sumimoto, F. Inagaki, Structure of a cell polarity regulator, a complex between atypical PKC and Par6 PB1 domains. J. Biol. Chem. 280, 9653–9661 (2005).
37.
S. Müller, I. Kursula, P. Zou, M. Wilmanns, Crystal structure of the PB1 domain of NBR1. FEBS Lett. 580, 341–344 (2006).
38.
K. Honbou, R. Minakami, S. Yuzawa, R. Takeya, N. N. Suzuki, S. Kamakura, H. Sumimoto, F. Inagaki, Full-length p40phox structure suggests a basis for regulation mechanism of its membrane binding. EMBO J. 26, 1176–1186 (2007).
39.
L. Gao, G. Joberty, I. G. Macara, Assembly of epithelial tight junctions is negatively regulated by Par6. Curr. Biol. 12, 221–225 (2002).
40.
D. Roos, M. de Boer, F. Kuribayashi, C. Meischl, R. S. Weening, A. W. Segal, A. Åhlin, K. Nemet, J. P. Hossle, E. Bernatowska-Matuszkiewicz, H. Middleton-Price, Mutations in the X-linked and autosomal recessive forms of chronic granulomatous disease. Blood 87, 1663–1681 (1996).
41.
H. Sumimoto, Y. Kage, H. Nunoi, H. Sasaki, T. Nose, Y. Fukumaki, M. Ohno, S. Minakami, K. Takeshige, Role of Src homology 3 domains in assembly and activation of the phagocyte NADPH oxidase. Proc. Natl. Acad. Sci. U.S.A. 91, 5345–5349 (1994).
42.
T. L. Leto, A. G. Adams, I. de Mendez, Assembly of the phagocyte NADPH oxidase: Binding of Src homology 3 domains to proline-rich targets. Proc. Natl. Acad. Sci. U.S.A. 91, 10650–10654 (1994).
43.
T. Ago, H. Nunoi, T. Ito, H. Sumimoto, Mechanism for phosphorylation-induced activation of the phagocyte NADPH oxidase protein p47phox. Triple replacement of serines 303, 304, and 328 with aspartates disrupts the SH3 domain-mediated intramolecular interaction in p47phox, thereby activating the oxidase. J. Biol. Chem. 274, 33644–33653 (1999).
44.
Y. Groemping, K. Lapouge, S. J. Smerdon, K. Rittinger, Molecular basis of phosphorylation-induced activation of the NADPH oxidase. Cell 113, 343–355 (2003).
45.
K. Kami, R. Takeya, H. Sumimoto, D. Kohda, Diverse recognition of non-PxxP peptide ligands by the SH3 domains from p67phox, Grb2 and Pex13p. EMBO J. 21, 4268–4276 (2002).
46.
C. Massenet, S. Chenavas, C. Cohen-Addad, M.-C. Dagher, G. Brandolin, E. Pebay-Peyroula, F. Fieschi, Effects of p47phox C terminus phosphorylations on binding interactions with p40phox and p67phox. Structural and functional comparison of p40phox and p67phox SH3 domains. J. Biol. Chem. 280, 13752–13761 (2005).
47.
R. Sarfstein, Y. Gorzalczany, A. Mizrahi, Y. Berdichevsky, S. Molshanski-Mor, C. Weinbaum, M. Hirshberg, M.-C. Dagher, E. Pick, Dual role of Rac in the assembly of NADPH oxidase, tethering to the membrane and activation of p67phox: A study based on mutagenesis of p67phox-Rac1 chimeras. J. Biol. Chem. 279, 16007–16016 (2004).
48.
C. H. Han, J. L. Freeman, T. Lee, S. A. Motalebi, J. D. Lambeth, Regulation of the neutrophil respiratory burst oxidase. Identification of an activation domain in p67phox. J. Biol. Chem. 273, 16663–16668 (1998).
49.
B. A. Diebold, G. M. Bokoch, Molecular basis for Rac2 regulation of phagocyte NADPH oxidase. Nat. Immunol. 2, 211–215 (2001).
50.
F. Kuribayashi, H. Nunoi, K. Wakamatsu, S. Tsunawaki, K. Sato, T. Ito, H. Sumimoto, The adaptor protein p40phox as a positive regulator of the superoxide-producing phagocyte oxidase. EMBO J. 21, 6312–6320 (2002).
51.
C. I. Suh, N. D. Stull, X. J. Li, W. Tian, M. O. Price, S. Grinstein, M. B. Yaffe, S. Atkinson, M. C. Dinauer, The phosphoinositide-binding protein p40phox activates the NADPH oxidase during FcγIIA receptor-induced phagocytosis. J. Exp. Med. 203, 1915–1925 (2006).
52.
C. D. Ellson, K. Davidson, G. J. Ferguson, R. O’Connor, L. R. Stephens, P. T. Hawkins, Neutrophils from p40phox–/– mice exhibit severe defects in NADPH oxidase regulation and oxidant-dependent bacterial killing. J. Exp. Med. 203, 1927–1937 (2006).
53.
F. Kanai, H. Liu, S. J. Field, H. Akbary, T. Matsuo, G. E. Brown, L. C. Cantley, M. B. Yaffe, The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nat. Cell Biol. 3, 675–678 (2001).
54.
C. D. Ellson, S. Gobert-Gosse, K. E. Anderson, K. Davidson, H. Erdjument-Bromage, P. Tempst, J. W. Thuring, M. A. Cooper, Z. Y. Lim, A. B. Holmes, P. R. Gaffney, J. Coadwell, E. R. Chilvers, P. T. Hawkins, L. R. Stephens, PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40phox. Nat. Cell Biol. 3, 679–682 (2001).
55.
T. Ago, R. Takeya, H. Hiroaki, F. Kuribayashi, T. Ito, D. Kohda, H. Sumimoto, The PX domain as a novel phosphoinositide-binding module. Biochem. Biophys. Res. Commun. 287, 733–738 (2001).
56.
Y. Inoue, M. Ogasawara, T. Moroi, M. Satake, K. Azumi, T. Moritomo, T. Nakanishi, Characteristics of NADPH oxidase genes (Nox2, p22, p47, and p67) and Nox4 gene expressed in blood cells of juvenile Ciona intestinalis. Immunogenetics 57, 520–534 (2005).
57.
K. Matsuno, H. Yamada, K. Iwata, D. Jin, M. Katsuyama, M. Matsuki, S. Takai, K. Yamanishi, M. Miyazaki, H. Matsubara, C. Yabe-Nishimura, Nox1 is involved in angiotensin II-mediated hypertension: A study in Nox1-deficient mice. Circulation 112, 2677–2685 (2005).
58.
A. Dikalova, R. Clempus, B. Lassègue, G. Cheng, J. McCoy, S. Dikalov, A. San Martin, A. Lyle, D. S. Weber, D. Weiss, W. R. Taylor, H. H. Schmidt, G. K. Owens, J. D. Lambeth, K. K. Griendling, Nox1 overexpression potentiates angiotensin II-induced hypertension and vascular smooth muscle hypertrophy in transgenic mice. Circulation 112, 2668–2676 (2005).
59.
B. Bánfi, R. A. Clark, K. Steger, K.-H. Krause, Two novel proteins activate superoxide generation by the NADPH oxidase NOX1. J. Biol. Chem. 278, 3510–3513 (2003).
60.
M. Geiszt, K. Lekstrom, J. Witta, T. L. Leto, Proteins homologous to p47phox and p67phox support superoxide production by NAD(P)H oxidase 1 in colon epithelial cells. J. Biol. Chem. 278, 20006–20012 (2003).
61.
R. Takeya, N. Ueno, K. Kami, M. Taura, M. Kohjima, T. Izaki, H. Nunoi, H. Sumimoto, Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases. J. Biol. Chem. 278, 25234–25246 (2003).
62.
T. Ueyama, M. Geiszt, T. L. Leto, Involvement of Rac1 in activation of multicomponent Nox1- and Nox3-based NADPH oxidases. Mol. Cell. Biol. 26, 2160–2174 (2006).
63.
G. Cheng, B. A. Diebold, Y. Hughes, J. D. Lambeth, Nox1-dependent reactive oxygen generation is regulated by Rac1. J. Biol. Chem. 281, 17718–17726 (2006).
64.
K. Miyano, N. Ueno, R. Takeya, H. Sumimoto, Direct involvement of the small GTPase Rac in activation of the superoxide-producing NADPH oxidase Nox1. J. Biol. Chem. 281, 21857–21868 (2006).
65.
R. Paffenholz, R. A. Bergstrom, F. Pasutto, P. Wabnitz, R. J. Munroe, W. Jagla, U. Heinzmann, A. Marquardt, A. Bareiss, J. Laufs, A. Russ, G. Stumm, J. C. Schimenti, D. E. Bergstrom, Vestibular defects in head-tilt mice result from mutations in Nox3, encoding an NADPH oxidase. Genes Dev. 18, 486–491 (2004).
66.
G. Cheng, D. Ritsick, J. D. Lambeth, Nox3 regulation by NOXO1, p47phox, and p67phox. J. Biol. Chem. 279, 34250–34255 (2004).
67.
N. Ueno, R. Takeya, K. Miyano, H. Kikuchi, H. Sumimoto, The NADPH oxidase Nox3 constitutively produces superoxide in a p22phox-dependent manner: Its regulation by oxidase organizers and activators. J. Biol. Chem. 280, 23328–23339 (2005).
68.
J. Aguirre, M. Rios-Momberg, D. Hewitt, W. Hansberg, Reactive oxygen species and development in microbial eukaryotes. Trends Microbiol. 13, 111–118 (2005).
69.
A. Tanaka, M. J. Christensen, D. Takemoto, P. Park, B. Scott, Reactive oxygen species play a role in regulating a fungus-perennial ryegrass mutualistic interaction. Plant Cell 18, 1052–1066 (2006).
70.
H. Lalucque, P. Silar, NADPH oxidase: An enzyme for multicellularity? Trends Microbiol. 11, 9–12 (2003).
71.
D. Takemoto, A. Tanaka, B. Scott, A p67Phox-like regulator is recruited to control hyphal branching in a fungal-grass mutualistic symbiosis. Plant Cell 18, 2807–2821 (2006).
72.
B. Lardy, M. Bof, L. Aubry, M. H. Paclet, F. Morel, M. Satre, G. Klein, NADPH oxidase homologs are required for normal cell differentiation and morphogenesis in Dictyostelium discoideum. Biochim. Biophys. Acta 1744, 199–212 (2005).
73.
S. L. Baldauf, The deep roots of eukaryotes. Science 300, 1703–1706 (2000).
74.
J. G. Williams, A. A. Noegel, L. Eichinger, Manifestations of multicellularity: Dictyostelium reports in. Trends Genet. 21, 392–398 (2005).
75.
K. Overmyer, M. Brosche, J. Kangasjarvi, Reactive oxygen species and hormonal control of cell death. Trends Plant Sci. 8, 335–342 (2003).
76.
T. Kawasaki, K. Henmi, E. Ono, S. Hatakeyama, M. Iwano, H. Satoh, K. Shimamoto, The small GTP-binding protein rac is a regulator of cell death in plants. Proc. Natl. Acad. Sci. U.S.A. 96, 10922–10926 (1999).
77.
J. Park, Y. Gu, Y. Lee, Z. Yang, Y. Lee, Phosphatidic acid induces leaf cell death in Arabidopsis by activating the Rho-related small G protein GTPase-mediated pathway of reactive oxygen species generation. Plant Physiol. 134, 129–136 (2004).
78.
R. J. Carol, S. Takeda, P. Linstead, M. C. Durrant, H. Kakesova, P. Derbyshire, S. Drea, V. Zarsky, L. Dolan, A RhoGDP dissociation inhibitor spatially regulates growth in root hair cells. Nature 438, 1013–1016 (2005).
79.
A. C. Butty, N. Perrinjaquet, A. Petit, M. Jaquenoud, J. E. Segall, K. Hofmann, C. Zwahlen, M. Peter, A positive feedback loop stabilizes the guanine-nucleotide exchange factor Cdc24 at sites of polarization. EMBO J. 21, 1565–1576 (2002).
80.
J. E. Irazoqui, A. S. Gladfelter, D. J. Lew, Scaffold-mediated symmetry breaking by Cdc42p. Nat. Cell Biol. 5, 1062–1070 (2003).
81.
M. P. Gulli, M. Jaquenoud, Y. Shimada, G. Niederhäuser, P. Wiget, M. Peter, Phosphorylation of the Cdc42 exchange factor Cdc24 by the PAK-like kinase Cla4 may regulate polarized growth in yeast. Mol. Cell 6, 1155–1167 (2000).
82.
I. Bose, J. E. Irazoqui, J. J. Moskow, E. S. Bardes, T. R. Zyla, D. J. Lew, Assembly of scaffold-mediated complexes containing Cdc42p, the exchange factor Cdc24p, and the effector Cla4p required for cell cycle-regulated phosphorylation of Cdc24p. J. Biol. Chem. 276, 7176–7186 (2001).
83.
Y. Shimada, P. Wiget, M. P. Gulli, E. Bi, M. Peter, The nucleotide exchange factor Cdc24p may be regulated by auto-inhibition. EMBO J. 23, 1051–1062 (2004).
84.
B. K. Han, L. M. Bogomolnaya, J. M. Totten, H. M. Blank, L. J. Dangott, M. Polymenis, Bem1p, a scaffold signaling protein, mediates cyclin-dependent control of vacuolar homeostasis in Saccharomyces cerevisiae. Genes Dev. 19, 2606–2618 (2005).
85.
H. Xu, W. Wickner, Bem1p is a positive regulator of the homotypic fusion of yeast vacuoles. J. Biol. Chem. 281, 27158–27166 (2006).
86.
M. Pardo, P. Nurse, The nuclear rim protein Amo1 is required for proper microtubule cytoskeleton organisation in fission yeast. J. Cell Sci. 118, 1705–1714 (2005).
87.
C. Martin-Castellanos, M. Blanco, A. E. Rozalén, L. Pérez-Hidalgo, A. I. Garcia, F. Conde, J. Mata, C. Ellermeier, L. Davis, P. San-Segundo, G. R. Smith, S. Moreno, A large-scale screen in S. pombe identifies seven novel genes required for critical meiotic events. Curr. Biol. 15, 2056–2062 (2005).
88.
A. Wodarz, Establishing cell polarity in development. Nat. Cell Biol. 4, E39–E44 (2002).
89.
K. Kemphues, PARsing embryonic polarity. Cell 101, 345–348 (2000).
90.
D. Henrique, F. Schweisguth, Cell polarity: The ups and downs of the Par6/aPKC complex. Curr. Opin. Genet. Dev. 13, 341–350 (2003).
91.
I. G. Macara, Parsing the polarity code. Nat. Rev. Mol. Cell Biol. 5, 220–231 (2004).
92.
A. Suzuki, S. Ohno, The PAR-aPKC system: Lessons in polarity. J. Cell Sci. 119, 979–987 (2006).
93.
Y. Izumi, T. Hirose, Y. Tamai, S. Hirai, Y. Nagashima, T. Fujimoto, Y. Tabuse, K. J. Kemphues, S. Ohno, An atypical PKC directly associates and colocalizes at the epithelial tight junction with ASIP, a mammalian homologue of Caenorhabditis elegans polarity protein PAR-3. J. Cell Biol. 143, 95–106 (1998).
94.
Y. Tabuse, Y. Izumi, F. Piano, K. J. Kemphues, J. Miwa, S. Ohno, Atypical protein kinase C cooperates with PAR-3 to establish embryonic polarity in Caenorhabditis elegans. Development 125, 3607–3614 (1998).
95.
T. J. Hung, K. J. Kemphues, PAR-6 is a conserved PDZ domain-containing protein that colocalizes with PAR-3 in Caenorhabditis elegans embryos. Development 126, 127–135 (1999).
96.
S. Aono, R. Legouis, W. A. Hoose, K. J. Kemphues, PAR-3 is required for epithelial cell polarity in the distal spermatheca of C. elegans. Development 131, 2865–2874 (2004).
97.
M. Petronczki, J. A. Knoblich, DmPAR-6 directs epithelial polarity and asymmetric cell division of neuroblasts in Drosophila. Nat. Cell Biol. 3, 43–49 (2001).
98.
A. Wodarz, A. Ramrath, A. Grimm, E. Knust, Drosophila atypical protein kinase C associates with Bazooka and controls polarity of epithelia and neuroblasts. J. Cell Biol. 150, 1361–1374 (2000).
99.
F. Matsuzaki, Asymmetric division of Drosophila neural stem cells: A basis for neural diversity. Curr. Opin. Neurobiol. 10, 38–44 (2000).
100.
C. Q. Doe, B. Bowerman, Asymmetric cell division: Fly neuroblast meets worm zygote. Curr. Opin. Cell Biol. 13, 68–75 (2001).
101.
Y. N. Jan, L. Y. Jan, Asymmetric cell division in the Drosophila nervous system. Nat. Rev. Neurosci. 2, 772–779 (2001).
102.
J. A. Knoblich, Asymmetric cell division during animal development. Nat. Rev. Mol. Cell Biol. 2, 11–20 (2001).
103.
W. Chia, X. Yang, Asymmetric division of Drosophila neural progenitors. Curr. Opin. Genet. Dev. 12, 459–464 (2002).
104.
A. Suzuki, T. Yamanaka, T. Hirose, N. Manabe, K. Mizuno, M. Shimizu, K. Akimoto, Y. Izumi, T. Ohnishi, S. Ohno, Atypical protein kinase C is involved in the evolutionarily conserved par protein complex and plays a critical role in establishing epithelia-specific junctional structures. J. Cell Biol. 152, 1183–1196 (2001).
105.
S. H. Shi, L. Y. Jan, Y. N. Jan, Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3-kinase activity. Cell 112, 63–75 (2003).
106.
J. P. Thiery, Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454 (2002).
107.
R. Bose, J. L. Wrana, Regulation of Par6 by extracellular signals. Curr. Opin. Cell Biol. 18, 206–212 (2006).
108.
B. Ozdamar, R. Bose, M. Barrios-Rodiles, H.-R. Wang, Y. Zhang, J. L. Wrana, Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science 307, 1603–1609 (2005).
109.
M. Barrios-Rodiles, K. R. Brown, B. Ozdamar, R. Bose, Z. Liu, R. S. Donovan, F. Shinjo, Y. Liu, J. Dembowy, I. W. Taylor, V. Luga, N. Przulj, M. Robinson, H. Suzuki, Y. Hayashizaki, I. Jurisica, J. L. Wrana, High-throughput mapping of a dynamic signaling network in mammalian cells. Science 307, 1621–1625 (2005).
110.
M. Kusakabe, E. Nishida, The polarity-inducing kinase Par-1 controls Xenopus gastrulation in cooperation with 14-3-3 and aPKC. EMBO J. 23, 4190–4201 (2004).
111.
A. J. Kay, C. P. Hunter, CDC-42 regulates PAR protein localization and function to control cellular and embryonic polarity in C. elegans. Curr. Biol. 11, 474–481 (2001).
112.
M. Gotta, M. C. Abraham, J. Ahringer, CDC-42 controls early cell polarity and spindle orientation in C. elegans. Curr. Biol. 11, 482–488 (2001).
113.
S. Etienne-Manneville, A. Hall, Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCζ. Cell 106, 489–498 (2001).
114.
S. Etienne-Manneville, A. Hall, Cdc42 regulates GSK-3β and adenomatous polyposis coli to control cell polarity. Nature 421, 753–756 (2003).
115.
A. Hutterer, J. Betschinger, M. Petronczki, J. A. Knoblich, Sequential roles of Cdc42, Par-6, aPKC, and Lgl in the establishment of epithelial polarity during Drosophila embryogenesis. Dev. Cell 6, 845–854 (2004).
116.
I. Joung, J. L. Strominger, J. Shin, Molecular cloning of a phosphotyrosine-independent ligand of the p56lck SH2 domain. Proc. Natl. Acad. Sci. U.S.A. 93, 5991–5995 (1996).
117.
J. Shin, P62 and the sequestosome, a novel mechanism for protein metabolism. Arch. Pharm. Res. 21, 629–633 (1998).
118.
A. Puls, S. Schmidt, F. Grawe, S. Stabel, Interaction of protein kinase C ζ with ZIP, a novel protein kinase C-binding protein. Proc. Natl. Acad. Sci. U.S.A. 94, 6191–6196 (1997).
119.
S. L. Marcus, C. J. Winrow, J. P. Capone, R. A. Rachubinski, A p56lck ligand serves as a coactivator of an orphan nuclear hormone receptor. J. Biol. Chem. 271, 27197–27200 (1996).
120.
T. Ishii, T. Yanagawa, T. Kawane, K. Yuki, J. Seita, H. Yoshida, S. Bannai, Murine peritoneal macrophages induce a novel 60-kDa protein with structural similarity to a tyrosine kinase p56lck-associated protein in response to oxidative stress. Biochem. Biophys. Res. Commun. 226, 456–460 (1996).
121.
A. Avila, N. Silverman, M. T. Diaz-Meco, J. Moscat, The Drosophila atypical protein kinase C-ref(2)p complex constitutes a conserved module for signaling in the toll pathway. Mol. Cell. Biol. 22, 8787–8795 (2002).
122.
N. Laurin, J. P. Brown, J. Morissette, V. Raymond, Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am. J. Hum. Genet. 70, 1582–1588 (2002).
123.
L. J. Hocking, G. J. Lucas, A. Daroszewska, J. Mangion, M. Olavesen, T. Cundy, G. C. Nicholson, L. Ward, S. T. Bennett, W. Wuyts, W. Van Hul, S. H. Ralston, Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget’s disease. Hum. Mol. Genet. 11, 2735–2739 (2002).
124.
A. Daroszewska, S. H. Ralston, Mechanisms of disease: Genetics of Paget’s disease of bone and related disorders. Nat. Clin. Pract. Rheumatol. 2, 270–277 (2006).
125.
A. Durán, M. Serrano, M. Leitges, J. M. Flores, S. Picard, J. P. Brown, J. Moscat, M. T. Diaz-Meco, The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev. Cell 6, 303–309 (2004).
126.
H. Hsu, D. L. Lacey, C. R. Dunstan, I. Solovyev, A. Colombero, E. Timms, H. L. Tan, G. Elliott, M. J. Kelley, I. Sarosi, L. Wang, X. Z. Xia, R. Elliott, L. Chiu, T. Black, S. Scully, C. Capparelli, S. Morony, G. Shimamoto, M. B. Bass, W. J. Boyle, Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc. Natl. Acad. Sci. U.S.A. 96, 3540–3545 (1999).
127.
W. McLean, B. R. Olsen, Mouse models of abnormal skeletal development and homeostasis. Trends Genet. 17, S38–S43 (2001).
128.
W. J. Boyle, W. S. Simonet, D. L. Lacey, Osteoclast differentiation and activation. Nature 423, 337–342 (2003).
129.
S. L. Teitelbaum, F. P. Ross, Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, 638–649 (2003).
130.
M. Leitges, L. Sanz, P. Martin, A. Duran, U. Braun, J. F. Garcia, F. Camacho, M. T. Diaz-Meco, P. D. Rennert, J. Moscat, Targeted disruption of the ζPKC gene results in the impairment of the NF-κB pathway. Mol. Cell 8, 771–780 (2001).
131.
P. Martin, A. Duran, S. Minguet, M.-L. Gaspar, M.-T. Diaz-Meco, P. Rennert, M. Leitges, J. Moscat, Role of ζPKC in B-cell signaling and function. EMBO J. 21, 4049–4057 (2002).
132.
R. S. Soloff, C. Katayama, M. Y. Lin, J. R. Feramisco, S. M. Hedrick, Targeted deletion of protein kinase C λ reveals a distribution of functions between the two atypical protein kinase C isoforms. J. Immunol. 173, 3250–3260 (2004).
133.
P. Martin, M. T. Diaz-Meco, J. Moscat, The signaling adapter p62 is an important mediator of T helper 2 cell function and allergic airway inflammation. EMBO J. 25, 3524–3533 (2006).
134.
P. Martin, R. Villares, S. Rodriguez-Mascarenhas, A. Zaballos, M. Leitges, J. Kovac, I. Sizing, P. Rennert, G. Márquez, A. C. Martinez, M. T. Diaz-Meco, J. Moscat, Control of T helper 2 cell function and allergic airway inflammation by PKCζ. Proc. Natl. Acad. Sci. U.S.A. 102, 9866–9871 (2005).
135.
K. Zatloukal, C. Stumptner, A. Fuchsbichler, H. Heid, M. Schnoelzer, L. Kenner, R. Kleinert, M. Prinz, A. Aguzzi, H. Denk, p62 is a common component of cytoplasmic inclusions in protein aggregation diseases. Am. J. Pathol. 160, 255–263 (2002).
136.
U. Nagaoka, K. Kim, N. R. Jana, H. Doi, M. Maruyama, K. Mitsui, F. Oyama, N. Nukina, Increased expression of p62 in expanded polyglutamine-expressing cells and its association with polyglutamine inclusions. J. Neurochem. 91, 57–68 (2004).
137.
T. Ishii, K. Itoh, S. Takahashi, H. Sato, T. Yanagawa, Y. Katoh, S. Bannai, M. Yamamoto, Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J. Biol. Chem. 275, 16023–16029 (2000).
138.
A. Hershko, A. Ciechanover, The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).
139.
Y. Ohsumi, Molecular dissection of autophagy: Two ubiquitin-like systems. Nat. Rev. Mol. Cell Biol. 2, 211–216 (2001).
140.
M. L. Seibenhener, J. R. Babu, T. Geetha, H. C. Wong, N. R. Krishna, M. W. Wooten, Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol. Cell. Biol. 24, 8055–8068 (2004).
141.
M. L. Seibenhener, T. Geetha, M. W. Wooten, Sequestosome 1/p62—more than just a scaffold. FEBS Lett. 581, 175–179 (2007).
142.
T. Hara, K. Nakamura, M. Matsui, A. Yamamoto, Y. Nakahara, R. Suzuki-Migishima, M. Yokoyama, K. Mishima, I. Saito, H. Okano, N. Mizushima, Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).
143.
M. Komatsu, S. Waguri, T. Chiba, S. Murata, J. Iwata, I. Tanida, T. Ueno, M. Koike, Y. Uchiyama, E. Kominami, K. Tanaka, Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).
144.
C. Stumptner, A. Fuchsbichler, H. Heid, K. Zatloukal, H. Denk, Mallory body—a disease-associated type of sequestosome. Hepatology 35, 1053–1062 (2002).
145.
M. W. Wooten, T. Geetha, M. L. Seibenhener, J. R. Babu, M. T. Diaz-Meco, J. Moscat, The p62 scaffold regulates nerve growth factor-induced NF-κB activation by influencing TRAF6 polyubiquitination. J. Biol. Chem. 280, 35625–35629 (2005).
146.
G. Bjørkøy, T. Lamark, A. Brech, H. Outzen, M. Perander, A. Øvervatn, H. Stenmark, T. Johansen, p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603–614 (2005).
147.
M. Komatsu, S. Waguri, T. Ueno, J. Iwata, S. Murata, I. Tanida, J. Ezaki, N. Mizushima, Y. Ohsumi, Y. Uchiyama, E. Kominami, K. Tanaka, T. Chiba, Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).
148.
S. Pankiv, T. Høyvarde Clausen, T. Lamark, A. Brech, J. A. Bruun, H. Outzen, A. Øvervatn, G. Bjørkøy, T. Johansen, p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282, 24131–24145 (2007).
149.
E. Nishida, Y. Gotoh, The MAP kinase cascade is essential for diverse signal transduction pathways. Trends Biochem. Sci. 18, 128–131 (1993).
150.
J. M. Kyriakis, J. Avruch, Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81, 807–869 (2001).
151.
S. Nishimoto, E. Nishida, MAPK signalling: ERK5 versus ERK1/2. EMBO Rep. 7, 782–786 (2006).
152.
A. Rodriguez, A. Durán, M. Selloum, M. F. Champy, F. J. Diez-Guerra, J. M. Flores, M. Serrano, J. Auwerx, M. T. Diaz-Meco, J. Moscat, Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62. Cell Metab. 3, 211–222 (2006).
153.
S. Kamakura, T. Moriguchi, E. Nishida, Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. J. Biol. Chem. 274, 26563–26571 (1999).
154.
K. Nakamura, G. L. Johnson, PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. J. Biol. Chem. 278, 36989–36992 (2003).
155.
J. Seyfried, X. Wang, G. Kharebava, C. Tournier, A novel mitogen-activated protein kinase docking site in the N terminus of MEK5α organizes the components of the extracellular signal-regulated kinase 5 signaling pathway. Mol. Cell. Biol. 25, 9820–9828 (2005).
156.
K. Nakamura, M. T. Uhlik, N. L. Johnson, K. M. Hahn, G. L. Johnson, PB1 domain-dependent signaling complex is required for extracellular signal-regulated kinase 5 activation. Mol. Cell. Biol. 26, 2065–2079 (2006).
157.
J. Yang, M. Boerm, M. McCarty, C. Bucana, I. J. Fidler, Y. Zhuang, B. Su, Mekk3 is essential for early embryonic cardiovascular development. Nat. Genet. 24, 309–313 (2000).
158.
X. Wang, A. J. Merritt, J. Seyfried, C. Guo, E. S. Papadakis, K. G. Finegan, M. Kayahara, J. Dixon, R. P. Boot-Handford, E. J. Cartwright, U. Mayer, C. Tournier, Targeted deletion of mek5 causes early embryonic death and defects in the extracellular signal-regulated kinase 5/myocyte enhancer factor 2 cell survival pathway. Mol. Cell. Biol. 25, 336–345 (2005).
159.
M. Hayashi, S. W. Kim, K. Imanaka-Yoshida, T. Yoshida, E. D. Abel, B. Eliceiri, Y. Yang, R. J. Ulevitch, J. D. Lee, Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure. J. Clin. Invest. 113, 1138–1148 (2004).
160.
Q. Lin, J. Schwarz, C. Bucana, E. N. Olson, Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276, 1404–1407 (1997).
161.
K. Nakamura, G. L. Johnson, Noncanonical function of MEKK2 and MEK5 PB1 domains for coordinated extracellular signal-regulated kinease 5 and c-Jun N-terminal kinase signaling. Mol. Cell. Biol. 27, 4566–4577 (2007).
162.
M. Mencinger, P. Aman, Characterization of TFG in mus musculus and Caenorhabditis elegans. Biochem. Biophys. Res. Commun. 257, 67–73 (1999).
163.
A. Greco, C. Mariani, C. Miranda, A. Lupas, S. Pagliardini, M. Pomati, M. A. Pierotti, The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a potential coiled-coil domain. Mol. Cell. Biol. 15, 6118–6127 (1995).
164.
L. Hernández, M. Pinyol, S. Hernández, S. Beà, K. Pulford, A. Rosenwald, L. Lamant, B. Falini, G. Ott, D. Y. Mason, G. Delsol, E. Campo, TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations. Blood 94, 3265–3268 (1999).
165.
E. Roccato, S. Pagliardini, L. Cleris, S. Canevari, F. Formelli, M. A. Pierotti, A. Greco, Role of TFG sequences outside the coiled-coil domain in TRK-T3 oncogenic activation. Oncogene 22, 807–818 (2003).
166.
A. Greco, L. Fusetti, C. Miranda, R. Villa, S. Zanotti, S. Pagliardini, M. A. Pierotti, Role of the TFG N-terminus and coiled-coil domain in the transforming activity of the thyroid TRK-T3 oncogene. Oncogene 16, 809–816 (1998).
167.
S. Lange, F. Xiang, A. Yakovenko, A. Vihola, P. Hackman, E. Rostkova, J. Kristensen, B. Brandmeier, G. Franzen, B. Hedberg, L. G. Gunnarsson, S. M. Hughes, S. Marchand, T. Sejersen, I. Richard, L. Edström, E. Ehler, B. Udd, M. Gautel, The kinase domain of titin controls muscle gene expression and protein turnover. Science 308, 1599–1603. Published online 31 March 2005.2005).
168.
L. Tskhovrebova, J. Trinick, Titin: Properties and family relationships. Nat. Rev. Mol. Cell Biol. 4, 679–689 (2003).
169.
T. Ueyama, T. Tatsuno, T. Kawasaki, S. Tsujibe, Y. Shirai, H. Sumimoto, T. L. Leto, N. Saito, A regulated adaptor function of p40phox: Distinct p67phox membrane targeting by p40phox and by p47phox. Mol. Biol. Cell 18, 441–454 (2007).
170.
A. Y. Borisov, L. H. Madsen, V. E. Tsyganov, Y. Umehara, V. A. Voroshilova, A. O. Batagov, N. Sandal, A. Mortensen, L. Schauser, N. Ellis, I. A. Tikhonovich, J. Stougaard, The Sym35 gene required for root nodule development in pea is an ortholog of Nin from Lotus japonicus. Plant Physiol. 131, 1009–1017 (2003).
171.
Supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by CREST of JST (Japan Science and Technology Agency).
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