BY0074-0010.indd Page 107 12/5/06 2:25:58 PM elhi /Volumes/ju108/POIN002/symbosia_indd%0
Biochem. Soc. Symp. 74, 107–116
(Printed in Great Britain)
© 2007 The Biochemical Society
10
The role of the
phosphoinositides at the
Golgi complex
Maria Antonietta De Matteis1 and Giovanni D’Angelo
Department of Cell Biology and Oncology, Consorzio Mario Negri Sud,
Via Nazionale 8/A, 66030 Santa Maria Imbaro, Chieti, Italy
Abstract
Eukaryotic cells are organized into a complex system of subcompartments,
each with its distinct protein and lipid composition. A continuous flux of membranes crosses these compartments, and in some cases direct connections exist
between the different organelles. It is thus surprising that they can maintain their
individual identities. Small GTPases and the phosphoinositides have emerged as
the key regulators in the maintenance of the identity of the Golgi complex. This
property is due to their ability to act either alone or, more often, in combination,
as cues directing and controlling the recruitment of proteins that possess phosphoinositide-binding domains. Among these many proteins there are the lipid
transfer proteins, which can transfer ceramide, oxysterol, cholesterol and possibly glucosylceramide. By regulating these lipid transfer proteins in this way, this
binomial combination of the small GTPases and the phosphoinositides acquires
a further important role: control of the synthesis and/or distribution of other
important integral constituents of cell organelles, such as the sphingolipids and
cholesterol. This role is particularly relevant at the level of the Golgi complex, a
key organelle in the biosynthesis, transport and sorting of both lipids and proteins that is located at the intersection of the secretory and endocytic pathways.
Introduction
The GC (Golgi complex) represents the central organelle of the secretory
pathway, in that it receives and exchanges membranes with the ER (endoplasmic
reticulum), the PM (plasma membrane) and the endosomal system. In mammalian
cells, the GC is organized as a ribbon that is made up of interconnected stacks
1
To whom correspondence should be addressed (e-mail [email protected]).
107
BY0074-0010.indd Page 108 12/5/06 2:25:59 PM elhi /Volumes/ju108/POIN002/symbosia_indd%0
108
M.A. De Matteis and G. D’Angelo
of flat cisternae. The cisternae at the cis side of the GC receive transport
intermediates carrying newly synthesized lipids and proteins (cargo) from the
ER. The cargo progresses through the Golgi stack in a cis-to-trans direction,
and at the TGN (trans-Golgi network) it is specifically sorted to different
destinations. Recently, it has been shown that the passage of cargo through
the stack elicits the formation of intercisternal connections [1]. Despite this
continuous flux of membranes and of these continuities, the Golgi cisternae
maintain their distinct compositions in terms of their lipid and protein
content [2]. Indeed, Golgi-resident proteins, such as the Golgi glycosylating
enzymes, have a polarized distribution across the stacks. In particular, the
enzymes involved in the remodelling of glycoproteins are distributed as
a cis-trans gradient according to their site and order of intervention on the
sugar chains.
The lipid composition of the different cisternae of the Golgi stacks is also
not homogeneous, with the early (cis) Golgi cisternae having a lipid content
closer to that of the ER [3] and the TGN having a lipid composition similar to
that of the PM and endosomes (which includes an enrichment in cholesterol and
the sphingolipids).
The maintenance of the identity of the GC itself and of the different
sub-Golgi compartments relies on multiple processes, which include the
retention and retrieval of specific lipid and protein components, the localized
recruitment of cytosolic proteins, and the generation of specific lipid species.
However, the mechanisms that are ultimately responsible for the maintenance
of the compartmentalization in the cell and the polarization of the cisternae
have not yet been precisely defined, and many factors appear to be involved.
Among these, the small GTPase ARF1 (ADP-ribosylation factor-1) and the
phosphoinositides have emerged as the key regulators of these processes
through their ability to spatially and temporally control the recruitment of
different molecular machineries via interactions with protein domains that
specifically bind the different phosphoinositide species [2]. These machineries
appear to directly control elementary steps in membrane trafficking (such
as budding and sorting), to mediate interactions with the cytoskeleton and
its related motor proteins, and to control the synthesis and distribution of key
lipid species, such as the sphoingolipids and cholesterol, as is seen for the lipid
transfer proteins.
ARF1 and the phosphoinositides at the Golgi complex
The small GTPase ARF1 has a central role in maintaining the identity,
structure and function of the GC [2]. This role is exemplified by the dismantling of the GC and its redistribution into the ER that is induced by the inactivation of ARF1 by the fungal toxin brefeldin A [4–6]. Given this important
role, it is not surprising that the activity of ARF1 is tightly controlled by a
series of factors that regulate its state of activation (i.e. its GTP-bound state)
through promotion of the exchange of GDP with GTP [the GEFs (guanine nucleotide exchange factors)], and of the hydrolysis of GTP into GDP [the GAPs
© 2007 The Biochemical Society
BY0074-0010.indd Page 109 12/5/06 2:25:59 PM elhi /Volumes/ju108/POIN002/symbosia_indd%0
Phosphoinositides at the Golgi complex
109
(GTPase activating proteins)] [7]. ARF1 exerts its central role in the GC by
acting on different effectors, which include, among others, coat and/or adaptor proteins, such as COPI (coatomer protein I), the GGAs [Golgi-associated
γ-adaptin ear homology domain Arf (ADP-ribosylation factor)-interacting
protein] and AP1 (activating protein 1) [8], and lipid-modifying enzymes,
such as PLD (phospholipase D) [9] and the phosphoinositide kinases (PtdInsKs;
both PtdIns4K and PtdInsP5K) [10]. The coat and adaptor proteins control the
cargo sorting into transport carriers, the budding of these carriers from the different levels of the stack, and the directed delivery to their different destinations
in both anterograde and retrograde directions.
Among the lipid species where their production is under the control
of ARF1, the phosphoinositides have been the focus of particular attention
over the last few years. Following on from the seminal work of Bob Michell
[11], where the phosphoinositides were originally identified as precursors of
important second messengers at the PM, they have now been shown to be
important signals themselves, which are generated and act not only at the
PM, but also within various intracellular membrane compartments. Indeed,
almost every organelle is endowed with its specific set of PtdInsKs and
PtdInsP phosphatases [12].
The GC contains many PtdInsKs (including PtdIns3Ks, PtdIns4Ks and
PtdInsP5Ks) and PtdInsP phosphatases [including PtdIns 3-phosphatase [13];
PtdIns 4-phosphatase, and the PtdIns 5-phosphatases OCRL (oculocerebrorenal syndrome of Lowe)-1 and the 75 kDa 5-phosphatase pharbin]. OCRL
is of particular relevance, since genetic defects in this protein lead to the
development of Lowe syndrome, a rare disease that results in severe impairment of the eyes, the central nervous system and the kidney [14]. The severe
consequences induced by the loss of this PtdIns 5-phosphatase that is localized
at the GC and the endosomes highlights the importance of the maintenance of
the correct balance of the different phosphoinositide species at the level of these
compartments [12].
The most-studied of the PtdInsKs at the GC are the PtdIns4Ks:
PtdIns4KIIα and PtdIns4KIIIβ. The latter is recruited to the GC membranes
by the GTP-bound form of ARF1 [10], and it can be activated in vitro by ARF1
[15]. In addition, ARF1 can interact directly with PtdIns4KIIIβ. Furthermore,
ARF1 can interact with the NCS (neuronal calcium sensor)-1 Ca2+-binding
protein that also regulates PtdIns4KIIIβ activity [16]. The interaction between
ARF1 and PtdIns4KIIIβ is also conserved in yeast, as synthetic lethality has
been reported for the yeast PtdIns4K Pik1p and Arf [17].
Thus the recruitment and activity of PtdIns4KIIIβ is controlled by the
GTPase ARF1. However, PtdIns4KIIIβ can, in turn, act on another GTPase,
Rab11, since it has been shown that PtdIns4KIIIβ recruits Rab11 to the GC
[18]. Also in this case the interaction will have important functional consequences, since it is conserved in yeast, where the interaction between Pik1p
and the yeast homologue of Rab11, Ypt31p, has been shown to be important for protein trafficking through the secretory pathway [19]. Finally, the
kinase activity of PtdIns4KIIIβ is also regulated by PKD (protein kinase D)mediated phosphorylation [20]. Less is known about the regulation of the
© 2007 The Biochemical Society
BY0074-0010.indd Page 110 12/5/06 2:25:59 PM elhi /Volumes/ju108/POIN002/symbosia_indd%0
110
M.A. De Matteis and G. D’Angelo
other Golgi-associated PtdIns4K, PtdIns4KIIα, although it is ARF-independent
and resides and acts in the endosomal compartments [10,21].
Therefore the activity of PtdIns4KIIIβ is required to maintain the structure
of the GC and to control the trafficking of cargo through and out of the GC
[10,22], while PtdIns4KIIα is involved in GC-to-PM and GC-to-endosome
trafficking and also acts at the late endosome level, where it controls the degradation of endocytosed epidermal growth factor [23].
The product of the activity of the PtdIns4Ks, PtdIns4P, is the substrate
of the PtdInsP5K, and thus the precursor of PtdIns(4,5)P2. Although the
molecular identity of the Golgi-specific PtdInsP5K remains to be defined, its
product, PtdIns(4,5)P2, has a role in the maintenance of both the structure and
function of the GC: it has been shown to be required to build and maintain the
architecture of the GC [24], for the biogenesis of post-Golgi carriers [24], and
for the transport of apically directed cargo to the PM [25]. For the effectors
of PtdIns(4,5)P2 at the GC, the actin–spectrin skeleton is particularly relevant,
considering its role both in the structure and the function of the GC [24,26,27].
In addition, PtdIns(4,5)P2 is an important co-factor for ARF-dependent PLD,
and a regulator of the ARF exchange factors [28].
At the same time, PtdIns4P is not just the precursor of PtdIns(4,5)P2.
Indeed, following studies originally carried out in yeast, it has become clear
in the last few years that PtdIns4P has its own functions and its own effectors, especially at the GC [29]. Among these, there are the OSBPs (oxysterolbinding proteins), the GPBP (Goodpasture antigen-binding protein)/CERT
(ceramide transfer protein), and the FAPPs (four-phosphate adaptor proteins): all of these proteins share a PH (pleckstrin homology) domain that
preferentially binds to PtdIns4P, while at least OSBP1 and the FAPPs also
bind to ARF1. The binding selectivities of these proteins are thus responsible
for their targeting to the GC, and in particular to the late Golgi and TGN.
Interestingly all of these proteins have also been implicated in and/or suggested to have a role in lipid sensing, transfer and metabolism. In the present
chapter, we individually analyse GPBP/CERT, OSBP1 and the FAPPs with
respect to their known functions and regulation.
CERT
In their search for a resistance factor to the toxin lisenin (which acts by
binding to surface sphingomyelin) in a cell clone (LY-A cells), Hanada and
colleagues identified a protein known as the GPBP. GPBP was shown to
be the cytosolic factor that is required for the transport of ceramide to the
GC, and thus for the synthesis of sphingomyelin; for this reason the GPBP
protein was renamed as CERT [30,31]. CERT is a 598 amino acid protein
that is expressed in a full-length form and as an alternatively spliced form
that lacks an exon of 78 bp that encodes a 26 amino acid, serine-rich region [32]. CERT has a PH domain at its N-terminus, a FFAT (two phenylalanines [FF] in an acidic tract) motif, and a START [steroidogenic
acute regulatory (StAR)-related lipid-transfer] domain at its C-terminus.
© 2007 The Biochemical Society
BY0074-0010.indd Page 111 12/5/06 2:25:59 PM elhi /Volumes/ju108/POIN002/symbosia_indd%0
Phosphoinositides at the Golgi complex
111
The CERT PH domain (CERT-PH) shares a remarkable sequence
similarity with the PH domains of OSBP1 and the FAPPs, and retains the
property of selectively binding PtdIns4P [33,34]. CERT-PH is critical for CERT
localization and function, as exemplified by the observation that its mutation in
Gly76 is responsible for the lack of function of CERT in the LY-A cell clone
that was originally found to be resistant to lisenin. A second GC binding site in
CERT-PH has not been formally demonstrated to date; however, its similarity
with the OSBP1 and FAPP PH domains (also at the level of the β-7 strand, that
has been proposed to drive the PH-domain interaction with ARF1 [35]) and
the restricted localization of CERT-PH to the TGN [36] suggest that similar
two-site binding that is mediated by PtdIns4P and ARF will also be involved in
its recruitment to the GC.
The FFAT motif is an ER-localization motif: indeed, it is known to target
soluble proteins to the ER by virtue of its binding to the type II transmembrane
ER proteins VAP-A and VAP-B [37,38]. The interaction between CERT and the
VAPs has also been shown to be modulated and enhanced, in particular, under
conditions in which sphingomyelin synthesis is stimulated by the
oxysterols [39].
The C-terminal ceramide binding domain of CERT is known as a START
domain, the prototype of which was originally described as a cholesterolbinding motif in the StAR protein [40–43]. With CERT, its C-terminal START
domain has been shown to bind ceramide, and not cholesterol or other
phospholipids [44]. An analysis of the intermembrane transfer of ceramide
has also demonstrated that the CERT START domain binds and transfers
D-erythro-ceramides with different N-acyl-chains, with a preference for C14,
C16, C18 and C20 ceramides. Moreover, CERT binds to fluorescent ceramide
analogues with a 1:1 stoichiometry, consistent with a monomeric lipid transport
mechanism [44].
Owing to its ability to transfer ceramide specifically from the ER to the late
Golgi, where sphingomyelin synthase I is located, CERT acquires a central role
in the biosynthesis of sphingomyelin (Figure 1). Indeed, the identification of a
protein like CERT provided an important answer to one of the main questions
in the field that stemmed from the observation that the production of sphingomyelin is largely independent of ER-to-Golgi membrane trafficking. It has,
however, also simultaneously stimulated a number of new questions (i) What
are the mechanisms that are responsible for the directionality of ceramide transport by CERT from the ER-to-Golgi, rather than in the opposite direction or to
other locations? (ii) How is the coordination between membrane trafficking and
sphingomyelin synthesis achieved? (iii) Does CERT have any direct or indirect
roles in membrane trafficking? Future work is needed to answer these questions.
OSBP1
OSBP1 is a member of a gene family that comprises 12 related proteins, known as the ORPs (OSBP-related proteins), and it was originally identified as a high-affinity cytosolic receptor for the oxysterols [45].
© 2007 The Biochemical Society
BY0074-0010.indd Page 112 12/5/06 2:25:59 PM elhi /Volumes/ju108/POIN002/symbosia_indd%0
112
M.A. De Matteis and G. D’Angelo
It is a soluble protein that has been shown to undergo translocation from a
cytosolic/vesicular compartment to the GC in CHO (Chinese hamster ovary)
cells challenged with exogenous 25-hydroxycholesterol [46].
Numerous and pleiotropic effects on cholesterol metabolism have been
reported upon overexpression of both wild-type and mutant forms of the
OSBPs [39,47]. However, possibly due to the redundancy of the members of
this protein family, a coherent picture of the role and mechanism of action
of OSBP1 in cholesterol homoeostasis is still missing. Recently, however, an
unexpected role of OSBP1 in signalling was reported by Anderson and colleagues
[48], who showed that due to its ability to bind cholesterol and to form a
complex with the pERK (extracellular-signal-regulated kinase)-phosphatases,
OSBP1 can control the state of ERK phosphorylation in response to changes
in cholesterol levels.
The domain organization of OSBP1 closely resembles that of CERT
since it contains a PH domain at its N-terminus, a FFAT motif and an oxysterol-binding domain at its C-terminus. The OSBP1 interaction with the
GC has been shown to involve its PH domain and to require both PtdIns4P
and ARF1 [34]; it is also important for the effects of OSBP1 on cholesterol
homoeostasis [47]. The OSBP1 interaction with the ER is mediated by the
binding of its FFAT motif to VAP-A [37,49]. This ability of OSBP1 to bind
to both the GC and the ER, together with the evidence that some of the
yeast OSBP homologues, like Osh1 and 2, are localized at the levels of contact
sites between the nuclear envelope and the vacuole, and between the ER and
the PM respectively [49], has raised the interesting possibility that OSBP1
acts at the level of the contact sites existing between the smooth ER and the
trans-Golgi cisterna in mammals [50].
Although many questions remain open as to the actual function of OSBP1
as a lipid transfer protein in mammals, and on its mode of action, important
hints may now be coming from the recent advances in the study of one of
the yeast oxysterol-binding proteins, Osh4/Kes1p. Osh4/Kes1p is one of the
seven yeast OSBP homologues that is able to bind the phosphoinositols
through a domain that is distinct from that which binds the sterols, although
it is devoid of a ‘classical’ PH domain [51]. Crystallographic analysis has
shown that Osh4p/Kes1p has a hydrophobic tunnel that can accommodate
sterols (25-OH oxysterol, ergosterol, cholesterol) and that is covered by a flexible
‘lid’. The authors of this study proposed that the conformational change induced
by sterol binding promotes the closure of this lid, and allows the transport
of the lipid-bound form through the aqueous environment. In contrast, the
apo-form of Osh4p/Kes1p exposes potential phospholipid-binding sites that
appear to be responsible for its targeting to sterol donor membranes [52].
In agreement with this model, it has also been shown that Osh4p/Kes1p
specifically promotes the non-vesicular transfer of cholesterol and ergosterol
between membranes in vitro and that this transfer is more efficient in the
presence of the phosphoinositides [53]. Moreover, in vivo, ergosterol transport
has been shown to be regulated by OSBP homologues [53,54].
Other studies of OSH4/KES1 have also uncovered a functional link
between the OSBPs and vesicle biogenesis at the GC. Indeed, OSH4 deletion
© 2007 The Biochemical Society
BY0074-0010.indd Page 113 12/5/06 2:26:00 PM elhi /Volumes/ju108/POIN002/symbosia_indd%0
Phosphoinositides at the Golgi complex
113
by-passed the requirement for SEC14 (a phosphatidylinositol/phosphatidylcholine transfer protein) in regulating vesicular transport at the GC, suggesting
that Osh4p/Kes1p and Sec14 regulate the secretory function of the GC through
acting on the same pathway [51]. Moreover, genome-wide screening has revealed
a role for OSH4/KES1 in cell-surface delivery of a reporter cargo [55].
FAPPs
FAPP1 and FAPP2 were so named after the observation that they specifically
bind PtdIns4P. The PH domains of the FAPPs have been shown to bind both
PtdIns4P and ARF1, and by the virtue of this binding, to drive the localization
of the full-length FAPPs to the GC.
Overexpression of the FAPP1 PH domain (FAPP1-PH) inhibits anterograde
trafficking of neosynthesized proteins from the TGN to the PM, while promoting tubulation of the TGN [56]. Also, knockdown of the FAPPs inhibits the
transport of neosynthesized cargo from the TGN to the PM in COS7 cells [56],
and of apical-membrane-destined cargo proteins in polarized MDCK (Madin–
Darby canine kidney) cells [57]. According to recent findings, the effects of a
knockdown of the FAPPs on intracellular trafficking can be ascribed mainly to
the function of FAPP2 ([57] and M. A. De Matteis and G. D’Angelo, unpublished work).
Human FAPP1 (hFAPP1) is a 300 amino acid protein with an N-terminus
PH domain and a putative proline-rich motif at its C-terminus, while hFAPP2
has 507 amino acids and is 80% identical with and 90% similar to hFAPP1
at the N-terminus. However, hFAPP2 differs from hFAPP1 at the C-terminus
due to its putative GLTP (glycolipid transfer protein) domain [56]. GLTP is
a 24 kDa cytosolic protein that selectively accelerates the intermembrane
transfer of glycolipids in vitro [58], and the C-terminal portion of hFAPP2
has 40% sequence identity with human GLTP. Even though the overall
similarity between this C-terminal portion of FAPP2 and GLTP is only partial,
the residues that have been shown to be important in the glycolipid transfer
activity of GLTP are all well conserved in FAPP2 [58]. Thus FAPP2 has in its
molecular structure the potential to act as a glucosylceramide transfer protein
that will possibly be involved in the biosynthesis of complex glycosphingolipids,
of which glucosylceramide is the common precursor. Indeed, the topology of
glucosylceramide is unique among the sphingolipids, since it is synthesized on
the cytosolic surface of the GC, at a site that could thus be accessible to a cytosolic
protein like FAPP2 (Figure 1). This glucosylceramide is then transported to the
later GC compartments, where after flipping onto the lumenal side due to activity
of a still-unspecified flippase, it is converted into lactosylceramide and complex
glycosphingolipids. The demonstration that FAPP2 is not just a putative, but is
an actual glucosylceramide transfer protein operating in the synthetic pathway
of complex glycolipids, remains a challenge for future studies. This would be of
particular relevance since the glycosphingolipids, together with sphingomyelin
and cholesterol, represent important constituents of the membranes of the
late-GC, endosome and PM.
© 2007 The Biochemical Society
BY0074-0010.indd Page 114 12/5/06 2:26:00 PM elhi /Volumes/ju108/POIN002/symbosia_indd%0
114
M.A. De Matteis and G. D’Angelo
Conclusion and future directions
Membrane trafficking and organelle identity are governed by many and
multiple intimate relationships between proteins and lipids. The secretory
pathway has been widely studied with respect to protein trafficking and the
protein-based trafficking machineries, while much less is known about the way
that the lipids are transported to their final destinations and how they reach
and maintain their uneven distributions in the cell. Indeed, the GC behaves as a
lipid asymmetry generator, providing the distinction between the pre-Golgi and
early-Golgi membranes, which are poor in sphingolipids and cholesterol, and
the late-Golgi and post-Golgi membranes, which are enriched in sphingolipids
and cholesterol.
The sorting of the different membrane constituents into transport carriers
that are destined for different acceptor organelles appears more to depend on
than to produce ‘lipid asymmetry’ [3]. Thus an intriguing hypothesis is that
non-vesicular lipid transport contributes significantly to the asymmetric lipid
distribution of the cell, and as a consequence, to membrane trafficking. In this
context, great advances were made with the identification of the lipid-transfer
proteins CERT and OSBP1, and with the demonstration or implication of their
roles in transporting cholesterol (OSBP1) and ceramide (CERT) (Figure 1).
The great challenges for the future are therefore to reveal the molecular mechanisms by which these lipid-transfer proteins regulate membrane
trafficking, and to provide a more integrated view of how the functions of the
different molecular machineries are coordinated at the organelle and cellular
levels. What at present remains certain is the pivotal role in this process that the
Figure 1 Schematic representation of the possible sites and modes
of action of the PtdIns4P-binding and Golgi-associated lipid transfer
proteins CERT, FAPP2 and OSBP1 (see text for details).
© 2007 The Biochemical Society
BY0074-0010.indd Page 115 12/5/06 2:26:00 PM elhi /Volumes/ju108/POIN002/symbosia_indd%0
Phosphoinositides at the Golgi complex
115
small GTPases and phosphoinositides have, as they are good candidates to drive
not only the elementary processes of membrane trafficking, but also the vectorial non-vesicular transfer of lipids.
We would like to thank C.P. Berrie for editorial assistance, R. Le Donne for artwork, and
the Italian Association for Cancer Research (AIRC, Milan, Italy) and Telethon Italia for
financial support.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
Trucco, A., Polishchuk, R.S., Martella, O., Di Pentima, A., Fusella, A., Di Giandomenico,
D., San Pietro, E., Beznoussenko, G.V., Polishchuk, E.V., Baldassarre, M. et al. (2004) Nat.
Cell Biol. 6, 1071–1081
Behnia, R. and Munro, S. (2005) Nature 438, 597–604
Holthuis, J.C., Pomorski, T., Raggers, R.J., Sprong, H. and Van Meer, G. (2001) Physiol.
Rev. 81, 1689–1723
Lippincott-Schwartz, J., Yuan, L.C., Bonifacino, J.S. and Klausner, R.D. (1989) Cell 56,
801–813
Helms, J.B. and Rothman, J.E. (1992) Nature 360, 352–354
Donaldson, J.G., Finazzi, D. and Klausner, R.D. (1992) Nature 360, 350–352
D’Souza-Schorey, C. and Chavrier, P. (2006) Nat. Rev. Mol. Cell Biol. 7, 347–358
Donaldson, J.G., Honda, A. and Weigert, R. (2005) Biochim. Biophys. Acta 1744, 364–373
Brown, H.A., Gutowski, S., Moomaw, C.R., Slaughter, C. and Sternweis, P.C. (1993) Cell
75, 1137–1144
Godi, A., Pertile, P., Meyers, R., Marra, P., Di Tullio, G., Iurisci, C., Luini, A., Corda,
D. and De Matteis, M.A. (1999) Nat. Cell Biol. 1, 280–287
Michell, R.H. (1975) Biochim. Biophys. Acta 415, 81–47
De Matteis, M.A. and Godi, A. (2004) Nat. Cell Biol. 6, 487–492
Guipponi, M., Tapparel, C., Jousson, O., Scamuffa, N., Mas, C., Rossier, C., Hutter, P.,
Meda, P., Lyle, R., Reymond, A. and Antonarakis, S.E. (2001) Hum. Genet. 109, 569–575
Suchy, S.F., Olivos-Glander, I.M. and Nussabaum, R.L. (1995) Hum. Mol. Genet. 4,
2245–2250
Haynes, L.P., Thomas, G.M. and Burgoyne, R.D. (2005) J. Biol. Chem. 280, 6047–6054
Zhao, X., Varnai, P., Tuymetova, G., Balla, A., Toth, Z.E., Oker-Blom, C., Roder, J.,
Jeromin A. and Balla T. (2001) J. Biol. Chem. 276, 40183–40189
Walch-Solimena, C. and Novick, P. (1999) Nat. Cell Biol. 1, 523–525
de Graaf, P., Zwart, W.T., van Dijken, R.A., Deneka, M., Schulz, T.K., Geijsen, N., Coffer,
P.J., Gadella, B.M., Verkleij, A.J., van der Sluijs, P. and van Bergen en Henegouwen, P.M.
(2004) Mol. Biol. Cell 15, 2038–2047
Sciorra, V.A., Audhya, A., Parsons, A.B., Segev, N., Boone, C. and Emr, S.D. (2005) Mol.
Biol. Cell 16, 776–793
Hausser, A., Storz, P., Martens, S., Link, G., Toker, A. and Pfizenmaier, K. (2005) Nat. Cell
Biol. 7, 880–886
Balla, A. and Balla, T. (2006) Trends Cell Biol. 16, 351–361
Bruns, J.R., Ellis, M.A., Jeromin, A. and Weisz, O.A. (2002) J. Biol. Chem. 277, 2012–2018
Wang, Y.J., Wang, J., Sun, H.Q., Martinez, M., Sun, Y.X., Macia, E., Kirchhausen, T.,
Albanesi, J.P., Roth, M.G. and Yin, H.L. (2003) Cell 114, 299–310
Sweeney, D.A., Siddhanta, A. and Shields, D. (2002) J. Biol. Chem. 277, 3030–3039
Guerriero, C.J., Weixel, K.M., Bruns, J.R. and Weisz, O.A. (2006) J. Biol. Chem. 281,
15376–15384
De Matteis, M.A. and Morrow, J.S. (2000) J. Cell Sci. 113, 2331–2343
Fucini, R.V., Navarrete, A., Vadakkan, C., Lacomis, L., Erdjument-Bromage, H., Tempst,
P. and Stamnes, M. (2000) J. Biol. Chem. 275, 18824–18829
Ktistakis, N.T., Brown, H.A., Waters, M.G., Sternweis, P.C. and Roth, M.G. (1996) J. Cell
Biol. 134, 295–306
De Matteis, M.A., Di Campli, A. and Godi, A. (2005) Biochim. Biophys. Acta 1744,
396–405
© 2007 The Biochemical Society
BY0074-0010.indd Page 116 12/5/06 2:26:01 PM elhi /Volumes/ju108/POIN002/symbosia_indd%0
116
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
M.A. De Matteis and G. D’Angelo
Raya, A., Revert, F., Navarro, S. and Saus J. (1999) J. Biol. Chem. 274, 12642–12649
Hanada, K., Kumagai, K., Yasuda, S., Miura, Y., Kawano, M., Fukasawa, M. and Nishijima,
M. (2003) Nature 426, 803–809
Raya, A., Revert-Ros, F., Martinez-Martinez, P., Navarro, S., Rosello, E., Vieites, B.,
Granero, F., Forteza, J. and Saus, J. (2000) J. Biol. Chem. 275, 40392–40399
Dowler, S., Currie, R.A., Campbell, D.G., Deak, M., Kular, G., Downes, C.P. and Alessi,
D.R. (2000) Biochem. J. 351, 19–31
Levine, T.P. and Munro S.. (2002) Curr. Biol. 12, 695–704
Roy, A. and Levine, T,P. (2004) J. Biol. Chem. 279, 44683–44689
Perry, R.J. and Ridgway, N.D. (2005) Biochim. Biophys. Acta 1734, 220–234
Wyles, J.P., McMaster, C.R. and Ridgway, N.D. (2002) J. Biol. Chem. 277, 29908–29918
Wyles, J.P. and Ridgway, N.D. (2004) Exp. Cell Res. 297, 533–547
Perry, R.J. and Ridgway, N.D. (2006) Mol. Biol. Cell 17, 2604–2616
Tsujishita, Y. and Hurley, J.H. (2000) Nat. Struct. Biol. 7, 408–414
Roderick, S.L., Chan, W.W., Agate, D.S., Olsen, L.R., Vetting, M.W., Rajashankar, K.R. and
Cohen, D.E. (2002), Nat. Struct. Biol. 9, 507–511
de Brouwer, A.P., Bouma, B., van Tiel, C.M., Heerma, W., Brouwers, J.F., Bevers, L.E.,
Westerman, J., Roelofsen, B. and Wirtz, K.W. (2001) Chem. Phys. Lipids 112, 109–119
Westerman, J., Wirtz, K.W., Berkhout, T., van Deenen, L.L., Radhakrishnan, R. and
Khorana, H.G. (1983) Eur. J. Biochem. 132, 441–449
Kumagai, K., Yasuda, S., Okemoto, K., Nishijima, M., Kobayashi, S. and Hanada, K. (2005)
J. Biol. Chem. 280, 6488–6495
Kandutsch, A.A. and Shown, E.P. (1981) J. Biol. Chem. 256, 13068–13073
Ridgway, N.D., Dawson, P.A., Ho, Y.K., Brown, M.S. and Goldstein, J.L. (1992) J. Cell
Biol. 116, 307–319
Lagace, T.A., Byers, D.M., Cook, H.W. and Ridgway, N.D. (1997) Biochem. J. 326,
205–213
Wang, P.Y., Weng, J. and Anderson, R.G. (2005) Science 307, 1472–1476
Loewen, C.J., Roy A. and Levine T.P. (2003) EMBO J. 22, 2025–2035
Mogelsvang, S., Marsh, B.J., Ladinsky, M.S. and Howell K.E. (2004) Traffic 5, 338–345
Fang, M., Kearns, B.G., Gedvilaite, A., Kagiwada, S., Kearns, M., Fung, M.K. and
Bankaitis, V.A. (1996) EMBO J. 15, 6447–6459
Im, Y.J., Raychaudhuri, S., Prinz, W.A. and Hurley, J.H. (2005) Nature 437, 154–158
Raychaudhuri, S., Im, Y.J., Hurley, J.H. and Prinz, W.A. (2006) J. Cell Biol. 173, 107–119
Sullivan, D.P, Ohvo-Rekila, H., Baumann, N.A., Beh, C.T. and Menon, A.K. (2006)
Biochem. Soc. Trans. 34, 356–358
Proszynski, T.J., Klemm, R.W., Gravert, M., Hsu, P.P., Gloor, Y., Wagner, J., Kozak, K.,
Grabner, H., Walzer, K., Bagnat, M., Simons, K. and Walch-Solimena, C. (2005) Proc. Natl.
Acad. Sci. U.S.A. 102, 17981–17986
Godi, A., Di Campli, A., Konstantakopoulos, A., Di Tullio, G., Alessi, D.R., Kular, G.S.,
Daniele, T., Marra, P., Lucocq, J.M. and De Matteis, M.A. (2004) Nat. Cell Biol. 6, 393–404
Vieira, O.V., Verkade, P., Manninen, A. and Simons, K. (2005) J. Cell Biol. 170, 521–526
Malinina, L., Malakhova, M.L., Teplov, A., Brown, R.E. and Patel, D.J. (2004) Nature. 430,
1048–1053
© 2007 The Biochemical Society