**6. References**


Enzymology and Regulation of ArfGAPs and ArfGEFs 209

Goldberg,J. (1999). Structural and functional analysis of the ARF1-ARFGAP complex reveals

Goldberg,J. (2000). Decoding of sorting signals by coatomer through a GTPase switch in the

Goldfinger,L.E., Han,J., Kiosses,W.B., Howe,A.K., and Ginsberg,M.H. (2003). Spatial

Ha,V.L., Bharti,S., Inoue,H., Vass,W.C., Campa,F., Nie,Z.Z., de Gramont,A., Ward,Y., and

Habermann,B. (2004). The BAR-domain family of proteins: a case of bending and binding?

Hafner,M., Schmitz,A., Grune,I., Srivatsan,S.G., Paul,B., Kolanus,W., Quast,T., Kremmer,E.,

Hernandez-Deviez,D.J., Roth,M.G., Casanova,J.E., and Wilson,J.M. (2004). ARNO and ARF6

Hurtado-Lorenzo,A., Skinner,M., El Annan,J., Futai,M., Sun-Wada,G.H., Bourgoin,S.,

Ismail,S.A., Vetter,I.R., Sot,B., and Wittinghofer,A. (2010). The Structure of an Arf-ArfGAP Complex Reveals a Ca(2+) Regulatory Mechanism. Cell *141*, 812-821. Jian,X.Y., Brown,P., Schuck,P., Gruschus,J.M., Balbo,A., Hinshaw,J.E., and Randazzo,P.A.

Kahn,R.A. (2011). GAPs:Terminator versus effector functions and the role(s) of ArfGAP1 in

Kahn,R.A., Bruford,E., Inoue,H., Logsdon,J.M., Nie,Z., Premont,R.T., Randazzo,P.A.,

Kahn,R.A. (2009). Toward a model for Arf GTPases as regulators of traffic at the Golgi. FEBS

functions in cell migration and invasion. J. Biol. Chem. *283*, 14915-14926. Ha,V.L., Luo,R.B., Nie,Z.Z., and Randazzo,P.A. (2008b). Contribution of AZAP-Type Arf

alpha 4 beta 1-dependent cell migration. J Cell Biol *162*, 731-741.

restriction of alpha 4 integrin phosphorylation regulates lamellipodial stability and

Randazzo,P.A. (2008a). ASAP3 is a focal adhesion-associated Arf GAP that

GAPs to Cancer Cell Migration and Invasion. Advances in Cancer Research, *101*, 1-

The membrane bending and GTPase-binding functions of proteins from the BAR-

Bauer,I., and Famulok,M. (2006). Inhibition of cytohesins by SecinH3 leads to

regulate axonal elongation and branching through downstream activation of phosphatidylinositol 4-phosphate 5-kinase alpha. Mol. Biol. Cell *15*, 111-120. Hsu,V.W. (2011). Role of ARFGAP1 in COPI vesicle biogenesis. Cellular Logistics *1,55-56*. Hsu,V.W., Lee,S.Y., and Yang,J.S. (2009). The evolving understanding of COPI vesicle

Casanova,J., Wildeman,A., Bechoua,S., Ausiello,D.A., Brown,D., and Marshansky,V. (2006). V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nature Cell Biol *8*, 124-

(2009). Autoinhibition of Arf GTPase-activating Protein Activity by the BAR

Satake,M., Theibert,A.B., Zapp,M.L., and Cassel,D. (2008). Consensus nomenclature for the human ArfGAP domain containing proteins. J. Cell Biol. *182*, 1039-1044. Kahn,R.A., Cherfils,J., Elias,M., Lovering,R.C., Munro,S., and Schurmann,A. (2006).

Nomenclature for the human Arf family of GTP-binding proteins: ARF, ARL, and

a role for coatomer in GTP hydrolysis. Cell *96*, 893-902.

COPI coat complex. Cell *100*, 671-679.

domain family. EMBO Reports *5*, 250-255.

hepatic insulin resistance. Nature *444*, 941-944.

formation. Nature Rev Mol Cell Biol *10*, 360-364.

Domain in ASAP1. J. Biol. Chem. *284*, 1652-1663.

vesicle biogenesis. Cellular Logistics *1, 49-51*.

SAR proteins. J Cell Biol *172*, 645-650.

Lett *583*, 3872-3879.

16

1U8.


Campa,F., Yoon,H.Y., Ha,V.L., Szentpetery,Z., Balla,T., and Randazzo,P.A. (2009). A PH

Casanova,J.E. (2007). Regulation of arf activation: the sec7 family of guanine nucleotide

Caumon,A.S., Vitale,N., Gensse,M., Galas,M.C., Casanova,J.E., and Bader,M.F. (2000).

Che,M.M., Boja,E.S., Yoon,H.-Y., Gruschus,J., Jaffe,H., Stauffer,S., Schuck,P., Fales,H.M., and

Cohen,L.A., Honda,A., Varnai,P., Brown,F.D., Balla,T., and Donaldson,J.G. (2007). Active

DiNitto,J.P., Delprato,A., Lee,M.T.G., Cronin,T.C., Huang,S., Guilherme,A., Czech,M.P., and

Donaldson,J.G. and Jackson,C.L. (2011). ARF family G proteins and their regulators: roles in

East,M.P. and Kahn,R.A. (2011). Models for the functions of Arf GAPs. Sem Cell & Dev. Biol.

Ehlers,J.P., Worley,L., Onken,M.D., and Harbour,J.W. (2005). DDEF1 is located in an

Esteban,P.F., Yoon,H.Y., Becker,J., Dorsey,S.G., Caprari,P., Palko,M.E., Coppola,V.,

Frank,S.R., Hatfield,J.C., and Casanova,J.E. (1998). Remodeling of the actin cytoskeleton is

Frigerio,G., Grimsey,N., Dale,M., Majoul,I., and Duden,R. (2007). Two human ARFGAPs

Fuss,B., Becker,T., Zinke,I., and Hoch,M. (2006). The cytohesin Steppke is essential for

Geiger,C., Nagel,W., Boehm,T., van Kooyk,Y., Figdor,C.G., Kremmer,E., Hogg,N.,

Gillingham,A.K. and Munro,S. (2007). The Small G Proteins of the Arf Family and Their

nucleotide exchange factor ARNO. Mol. Biol. Cell *9*, 3133-3146.

associated with COP-I-coated vesicles. Traffic *8*, 1644-1655.

insulin signalling in Drosophila. Nature *444*, 945-948.

interaction with LFA-1. EMBO J *19*, 2525-2536.

Regulators. Ann Rev Cell Dev Biol *23*, 579-611.

28083.

exchange factors. Traffic *8*, 1476-1485.

pathway. J. Biol. Chem. *275*, 15637-15644.

Biol. Cell *18*, 2244-2253.

Canc Res *11*, 3609-3613.

tamalin. J Cell Biol *173*, 291-299.

*28*, 569-583.

375.

*22*, 3-9.

Domain in the Arf GTPase-activating Protein (GAP) ARAP1 Binds Phosphatidylinositiol 3,4,5-Trisphosphate and Regulates Arf GAP Activity Independently of Recruitment to the Plasma Membranes. J. Biol. Chem. *284*, 28069-

Identification of a plasma membrane-associated guanine nucleotide exchange factor for ARF6 in chromaffin cells - Possible role in the regulated exocytotic

Randazzo,P.A. (2005). Regulation of ASAP1 by phospholipids is dependent on the interface between the PH and Arf GAP domains. Cellular Signalling *17*, 1276-1288.

Arf6 recruits ARNO/cytohesin GEFs to the PM by binding their PH domain. Mol.

Lambright,D.G. (2007). Structural basis and mechanism of autoregulation in 3 phosphoinositide-dependent Grp1 family Arf GTPase exchange factors. Mol. Cell

membrane transport, development and disease. Nature Rev Mol Cell Biol *12*, 362-

amplified region of chromosome 8q and is overexpressed in uveal melanoma. Clin

Saragovi,H.U., Randazzo,P.A., and Tessarollo,L. (2006). A kinase-deficient TrkC receptor isoform activates Arf6-Rac1 signaling through the scaffold protein

coordinately regulated by protein kinase C and the ADP-ribosylation factor

Zeitlmann,L., Dierks,H., Weber,K.S.C., and Kolanus,W. (2000). Cytohesin-1 regulates beta-2 integrin-mediated adhesion through both ARF-GEF function and


Enzymology and Regulation of ArfGAPs and ArfGEFs 211

Nie,Z.Z. and Randazzo,P.A. (2006). Arf GAPs and membrane traffic. J Cell Sci *119*, 1203-

Nie,Z.Z., Stanley,K.T., Stauffer,S., Jacques,K.M., Hirsch,D.S., Takei,J., and Randazzo,P.A.

Onodera,Y., Hashimoto,S., Hashimoto,A., Morishige,M., Yamada,A., Ogawa,E., Adachi,M.,

Randazzo,P.A. (1997). Resolution of two ADP-ribosylation factor 1 GTPase-activating

Randazzo,P.A., Andrade,J., Miura,K., Brown,M.T., Long,Y.Q., Stauffer,S., Roller,P., and

Randazzo,P.A. and Hirsch,D.S. (2004). Arf GAPs: multifunctional proteins that regulate membrane traffic and actin remodelling. Cellular Signalling *16*, 401-413. Randazzo,P.A. and Kahn,R.A. (1994). GTP hydrolysis by ADP-ribosylation factor (Arf) is

Renault,L., Guibert,B., and Cherfils,J. (2003). Structural snapshots of the mechanism and inhibition of a guanine nucleotide exchange factor. Nature *426*, 525-530. Sabe,H., Onodera,Y., Mazaki,Y., and Hashimoto,S. (2006). ArfGAP family proteins in cell adhesion, migration and tumor invasion. Curr Opin Cell Biol *18*, 558-564. Sakurai,A., Gavard,J., nnas-Linhares,Y., Basile,J.R., Amornphimoltham,P., Palmby,T.R.,

Sakurai,A., Jian,X., Lee,C.J., Manavski,Y., Chavakis,E., Donaldson,J., Randazzo,P.A., and

Santy,L.C. and Casanova,J.E. (2001). Activation of ARF6 by ARNO stimulates epithelial cell

Scheffzek,K., Ahmadian,M.R., and Wittinghofer,A. (1998). GTPase-activating proteins:

Shiba,Y., Luo,R.B., Hinshaw,J.E., Szul,T., Hayashi,R., Sztul,E., Nagashima,K., Baxa,U., and

Spang,A., Shiba,Y., and Randazzo,P.A. (2010). Arf GAPs: Gatekeepers of vesicle generation.

Terui,T, Kahn,RA., and Randazzo,P.A. (1994). Effects of acid phospholipids on nucleotide

with phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. *269*, 28130-28135.

coatomer polymerization . Cellular Logistics *1, 139-154.*.

(2002). AGAP1, an endosome-associated, phosphoinositide-dependent ADPribosylation factor GTPase-activating protein that affects actin cytoskeleton. J. Biol.

SakuraiT., Manabe,T., Wada,H., Matsuura,N., and Sabe,H. (2005). Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive

Cooper,J.A. (2000). The Arf GTPase-activating protein ASAP1 regulates the actin

dependent on both an Arf GAP and acid phospholipids. J. Biol. Chem. *269*, 10758-

Yagi,H., Zhang,F., Randazzo,P.A., Li,X.R., Weigert,R., and Gutkind,J.S. (2010). Semaphorin 3E Initiates Antiangiogenic Signaling through Plexin D1 by Regulating

Gutkind,J.S. (2011). Phosphatidylinositol-4-phosphate 5-Kinase and GEP100/Brag2 Protein Mediate Antiangiogenic Signaling by Semaphorin 3E-Plexin-D1 through

migration through downstream activation of both Rac1 and phospholipase D. J Cell

helping hands to complement an active site. Trends in Biochemical Sciences *23*,

Randazzo,P.A. (2011). ArfGAP1 promotes COPI vesicle formation by facilitating

exchange properties of ADP-ribosylation factor-1 - Evidence for specific interaction

1211.

10763.

Biol *154*, 599-610.

FEBS Lett *584*, 2646-2651.

257-262.

Chem. *277*, 48965-48975.

activities. EMBO J *24*, 963-973.

proteins from rat liver. Biochem J *324*, 413-419.

Arf6 and R-Ras. Mol. Cell. Biol. *30*, 3086-3098.

Arf6 Protein. J. Biol. Chem. *286*, 34335-34345.

cytoskeleton. Proc Nat'l Acad Sci USA*97*, 4011-4016.


Kam,J.L., Miura,K., Jackson,T.R., Gruschus,J., Roller,P., Stauffer,S., Clark,J., Aneja,R., and

Localization and Regulation by the COPI Coat. Mol. Biol. Cell *20*, 859-869. Kruljac-Letunic,A., Moelleken,J., Kallin,A., Wieland,F., and Blaukat,A. (2003). The tyrosine

Lee,S.Y., Yang,J.S., Hong,W.J., Premont,R.T., and Hsu,V.W. (2005). ARFGAP1 plays a central

Luo,R., Ahvazi,B., Amariei,D., Shroder,D., Burrola,B., Losert,W., and Randazzo,P.A. (2007).

Luo,R., Ha,V.L., Hayashi,R., and Randazzo,P.A. (2009). Arf GAP2 is positively regulated by

Luo,R., Jenkins,L.M.M., Randazzo,P.A., and Gruschus,J. (2008). Dynamic interaction

Luo,R.B. and Randazzo,P.A. (2008). Kinetic analysis of Arf GAP1 indicates a regulatory role

Mazelova,J., stuto-Gribble,L., Inoue,H., Tam,B.M., Schonteich,E., Prekeris,R., Moritz,O.L.,

McMahon,H.T. and Gallop,J.L. (2005). Membrane curvature and mechanisms of dynamic

Merkulova,M., Bakulina,A., Thaker,Y.R., Gruber,G., and Marshansky,V. (2010). Specific

Merkulova,M., Hurtado-Lorenzo,A., Hosokawa,H., Zhuang,Z.J., Brown,D., Ausiello,D.A.,

Nie,Z., Hirsch,D.S., Luo,R., Jian,X., Stauffer,S., Cremesti,A., Andrade,J., Lebowitz,J.,

Nie,Z.Z., Fei,J., Premont,R.T., and Randazzo,P.A. (2005). The Arf GAPs AGAP1 and AGAP2

GTPase-activating protein ASAP1. J. Biol. Chem. *278*, 29560-29570.

coatomer and cargo. Cellular Signalling *21*, 1169-1179.

of a trafficking module through Arf4. EMBO J *28*, 183-192.

domains of ARNO. Biochim Biophys ACTA *1797*, 1398-1409.

of Epidermal Growth Factor Receptor. Curr Biol *16*, 130-139.

Biochem J *402*, 439-447.

*5*, 513-521.

3555-3566.

Cellular Signalling *20*, 1968-1977.

for coatomer. J. Biol. Chem. *283*, 21965-21977.

cell membrane remodelling. Nature *438*, 590-596.

Randazzo,P.A. (2000). Phosphoinositide-dependent activation of the ADPribosylation factor GTPase-activating protein ASAP1 - Evidence for the pleckstrin homology domain functioning as an allosteric site. J. Biol. Chem. *275*, 9653-9663. Kliouchnikov,L., Bigay,J., Mesmin,B., Parnis,A., Rawet,M., Goldfeder,N., Antonny,B., and

Cassel,D. (2009). Discrete Determinants in ArfGAP2/3 Conferring Golgi

kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-

role in coupling COPI cargo sorting with vesicle formation. J Cell Biol *168*, 281-290.

Kinetic analysis of GTP hydrolysis catalysed by the Arf1-GTP-ASAP1 complex.

between Arf GAP and PH domains of ASAP1 in the regulation of GAP activity.

Randazzo,P.A., and Deretic,D. (2009). Ciliary targeting motif VxPx directs assembly

motifs of the V-ATPase a2-subunit isoform interact with catalytic and regulatory

and Marshansky,V. (2011). Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution. Am J Physiol *300*, C1442-C1455. Nagel,W., Zeitlmann,L., Schilcher,P., Geiger,C., Kolanus,J., and Kolanus,W. (1998).

Phosphoinositide 3-OH kinase activates the beta(2) integrin adhesion pathway and induces membrane recruitment of cytohesin-1. J. Biol. Chem. *273*, 14853-14861. Nie,Z., Boehm,M., Boja,E., Vass,W., Bonifacino,J., Fales,H., and Randazzo PA (2003). Specific

Regulation of the Adaptor Protein Complex AP-3 by the Arf GAP AGAP1. Dev Cell

Marino,M., Ahvazi,B., Hinshaw,J.E., and Randazzo,P.A. (2006). A BAR domain in the N Terminus of the Arf GAP ASAP1 affects membrane structure and trafficking

distinguish between the adaptor protein complexes AP-1 and AP-3. J Cell Sci *118*,


**10** 

*Japan* 

**Metal Ion Homeostasis Mediated by NRAMP** 

**Increased Resistance to Iron and Cadmium Ion** 

Plants have developed several adaptive systems to control the cellular concentrations of essential metals in which the ion transporters play significant roles. At the cell surface, transporters localized on plasmamembrane controlled metal ion uptake and release whereas inside of the plant cells, those localized on endomembrane sequestered and remobilized metal ions in organella, such as vacuoles and plastids (Pilon et al. 2009, Puig and Peñarrubia, 2009). Iron is one of several essential nutrients but a problematic one for living organisms (Conte and Walker 2011). At the cellular level, iron is used as a cofactor in enzymatic activities based on the reversible reaction between Fe2+ (ferrous) and Fe3+ (ferric) ions (Hell and Stephan 2003). In plants, it is essential for chlorophyll synthesis and hence iron deficiency results in chlorosis and pale-yellow or white leaves (Wiedenhoeft 2006). Usually, iron is chelated to organic matter in insoluble forms in soils that causes iron deficiency whereas in anaerobic and acidic conditions, iron toxicity occurs because of the increase of iron solubility (Ricachenevsky et al. 2010). The basis of iron toxicity was usually discussed to be oxidative stress by generation of reactive-hydroxyl radicals (Neyens and Baeyens 2003). Iron homeostasis in plant cells is partly achieved through the control of iron transport across membranous structures, and several families of putative iron transporters, including ZIP (ZRT, IRT-like proteins) and NRAMP (natural resistance associated macrophage protein), have been described (Guerinot 2000, Curie and Briat 2003, Kim and Guerinot 2007). Among the ZIP transporters, the *Arabidopsis AtIRT1* was the first iron transport molecule identified in plants (Eide et al. 1996) and was shown to be the major transporter mediating iron uptake into roots (Vert et al. 2002). Recently, IRT2, a close homolog of IRT1 in *Arabidopsis*, was suggested to compartmentalize iron into vesicles to prevent toxicity from excess free iron in the cytosol (Vert et al. 2009). On the other hand, among the ubiquitous NRAMP family of

**1. Introduction** 

**Transporters in Plant Cells – Focused on** 

Masa H. Sato3, Toshiyuki Nagata1 and Seiichiro Hasezawa2,4

Toshio Sano1, Toshihiro Yoshihara1, Koichi Handa2,

*1Faculty of Bioscience and Applied Chemistry, Hosei University 2Graduate School of Frontier Sciences, The University of Tokyo* 

*3Graduate School of Life and Environmental Sciences,* 

*Kyoto Prefectural University* 

*4Advanced Measurement and Analysis, Japan Science and Technology Agency (JST)* 

