Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA
Author for correspondence (e-mail:
gutmannd{at}neuro.wustl.edu)
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Summary |
---|
Key words: Merlin, DAL-1, Tumor suppressor, Schwannomin
![]() |
Introduction |
---|
The Protein 4.1 superfamily has grown significantly since the
identification of the original founding member, with more then 40 members
identified to date. On the basis of protein sequence similarity, this
superfamily can be classified into five subgroups: Protein 4.1 molecules, ERM
proteins, talin-related molecules, PTPH (protein
tyrosine phosphatases) proteins and NBL4
(novel band 4.1-like 4)
(Takeuchi et al., 1994)
proteins (Fig. 1). Talin is a
200 kDa protein concentrated at focal contacts, where it has been hypothesized
to modulate binding of integrins to the cytoskeleton
(Burridge and Connell, 1983
).
Unlike other Protein 4.1 molecules, PTPH and NBL4 proteins lack characterized
actin-binding domains. The PTPH family includes at least three protein
tyrosine phosphatases containing an N-terminal FERM domain and a C-terminal
phosphatase domain (Gu et al.,
1991
). Localization of PTP-BL (protein-tyrosine
phosphatase-BAS-like) to the apical side of epithelial cells requires the FERM
domain (Cuppen et al., 1999
).
Another PTPH protein, PTP-FERM, is present in neuronal processes, where it
localizes to the peri-membrane region through its FERM domain
(Uchida et al., 2002
). NBL4
proteins contain an N-terminal FERM domain and a unique non-homologous
C-terminus (Takeuchi et al.,
1994
). A novel member of the NBL4 family (EHM2) has been
implicated in melanoma tumor metastasis
(Shimizu et al., 2000
).
|
In addition to linking cell surface proteins to the actin cytoskeleton, members of the Protein 4.1 family have an additional function: the neurofibromatosis 2 (NF2) gene product, merlin/schwannomin, and Protein 4.1B/DAL-1 are negative growth regulators (tumor suppressors). This unique function of Protein 4.1 molecules is the focus of this article.
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The Protein 4.1 and ERM subfamilies |
---|
|
The Protein 4.1 family includes Protein 4.1R (erythrocyte), Protein 4.1G
(general), Protein 4.1N (neuronal) and Protein 4.1B (brain). Each protein has
a distinct expression pattern and is encoded by individual genes
[Table 1
(Peters et al., 1998;
Parra et al., 2000
)]. This
family of proteins is characterized by the presence of three highly conserved
domains: an N-terminal FERM domain, a spectrin-actin-binding domain (SABD),
and a C-terminal domain (CTD, Fig.
1). In addition to these conserved domains, 4.1 proteins possess
several unique domains: U1, U2 and U3. Although the functions of these domains
are not known, their sequences are distinct from each other and thus might
specify unique protein interactions that underlie the functional differences
between Protein 4.1 family members.
One of the main functions of Protein 4.1 family members is the structural
stabilization of the cell membrane, which has been extensively characterized
in the erythrocyte. A decrease in 4.1R expression as a consequence of a
chromosomal mutation results in hereditary elliptocytosis, a disorder
characterized by pronounced hemolysis, splenomegaly and abnormally shaped red
blood cells (Tchernia et al.,
1981). This abnormal erythrocyte phenotype has also been
documented in Protein 4.1R null mice (Shi
et al., 1999
). Consistent with a role in membrane stabilization,
the FERM, SABD and CTD domains have been shown to mediate
membrane-cytoskeleton interactions through interactions with integral membrane
proteins. Protein 4.1 interacts with the Band 3 protein
(Pasternack et al., 1985
),
glycophorin C and glycophorin D (Hemming
et al., 1994
; Marfatia et al.,
1995
), p55 (Marfatia et al.,
1995
; Pasternack et al.,
1985
), CD44 (Nunomura et al.,
1997
) and calmodulin (Tanaka
et al., 1991
) through N-terminal FERM domain sequences. Protein
4.1 binds spectrin and actin and potentiates interactions of spectrin
tetramers with F-actin through its SABD
(Ohanian et al., 1984
),
whereas Protein 4.1N does not interact with spectrin
(Gimm et al., 2002
). Protein
4.1 molecules also associate with tubulin through SABD sequences
(Correas and Avila, 1988
) and
with FKBP13 (13 kDa FK506-binding protein)
(Walensky et al., 1998
)
through CTD residues. As a result of these interactions, Protein 4.1 molecules
play important structural and regulatory roles in the stabilization and
assembly of the cell membrane. The association of Protein 4.1 with
spectrin/actin and glycophorin C/p55 complexes appears to be essential for the
maintenance of normal erythrocyte morphology, and the interaction with tubulin
suggests that Protein 4.1 molecules may regulate microtubule architecture.
Protein 4.1 molecules also exhibit unique binding properties and
differentially associate with a variety of proteins. Protein 4.1R interacts
with the novel centrosomal protein CPAP
(Hung et al., 2000), the
eukaryotic translation initiation factor 3 (eIF3) complex
(Hou et al., 2000
), the zona
occludens protein ZO-2 (Mattagajasingh et
al., 1999
) and the pIc 1n protein involved in cellular volume
regulation (Tang and Tang,
1998
). In contrast, Protein 4.1N associates with the nuclear
mitotic apparatus protein NuMA (Ye et
al., 1999
), regulates AMPA receptor GluR1 subunit surface
expression (Shen et al., 2000
)
and binds to a nuclear phosphoinositide 3-kinase enhancer protein
(Ye et al., 2000
).
Members of the ERM family contain three main domains, including a FERM
domain or N-terminal ERM association domain (N-ERMAD) and a C-terminal
actin-binding domain (C-ERMAD), which are separated by a predicted coiled-coil
(-helical) domain (Fig.
1). Structural studies of the FERM domain of moesin revealed that
it has three distinct subdomains: F1, F2 and F3
(Edwards and Keep, 2001
). F1
shares structural features with ubiquitin, and F2 is homologous to
acyl-CoA-binding proteins, whereas F3 shares sequence similarity with
phosphotyrosine binding (PTB), pleckstrin homology (PH) and Enabled/VASP
homology 1 (EVH1) domains.
ERM proteins can form intramolecular and intermolecular associations that
are regulated by protein phosphorylation or lipid interactions. There are two
intramolecular associations: one between the N-terminus and the C-terminus and
the other within the N-terminus domain itself. The N-terminal 300-residue
FERM domain of ERM molecules can tightly associate with the C-terminal
100 residues of other ERM proteins
(Gary and Bretscher, 1995
;
Magendantz et al., 1995
). In a
hypophosphorylated state, ERM proteins adopt a `closed' conformation that
masks the binding sites for actin and CD44
(Hirao et al., 1996
).
Phosphorylation separates the N- and C-termini to result in an `open' form,
which permits interactions with the actin cytoskeleton and other proteins
(Pearson et al., 2000
). In
this manner, phosphorylation of ezrin (Thr567), radixin (Thr564) or moesin
(Thr558) by Rho kinase reduces the interaction between its N- and C-termini
(Matsui et al., 1998
).
Furthermore, mutations in moesin that mimic Thr558 phosphorylation result in
the formation of persistent microvillar structures
(Oshira et al., 1998
),
suggesting that phosphorylation-dependent `unfolding' of ERM proteins is
important for their ability to modulate actin-cytoskeleton-associated
processes. Lipid binding can also modulate these intramolecular associations.
Binding of the FERM domain to phosphatidylinositol (4,5)-bisphosphate
[PtdIns(4,5)P2] stimulates unfolding of ERM proteins and
their subsequent association with adhesion proteins
(Hamada et al., 2000
).
ERM proteins also associate with several types of transporter molecule
through PDZ domain sequences present in these transporters. EBP50 (ERM-binding
phosphoprotein 50), also known as NHERF1 (Na+/H+
exchanger regulatory factor 1), is a homologue of a rabbit protein cofactor
involved in renal brush-border Na+/H+ exchange. EBP50
colocalizes with actin and ERM proteins in actin-rich structures and can be
immunoprecipitated with ERM proteins from placental microvilli.
(Reczek et al., 1997;
Murthy et al., 1998
;
Nguyen et al., 2001
). Another
PDZ-containing protein, E3KARP (exchanger 3
kinase A regulatory protein) or
NHERF2, binds the N-terminus of ERM proteins
(Yun et al., 1998
;
Voltz et al., 2001
). The
binding sites for EBP50 and E3KARP in full-length ezrin are masked by
intramolecular N/C-ERMAD self-association. Growth factors stimulate the
phosphorylation of a C-terminal residue in ezrin (and moesin), resulting in
ezrin activation (Bretscher,
1999
). Upon activation, ezrin unfolds and can then bind
EBP50/E3KARP through N-terminal residues and F-actin through C-terminal
residues (Reczek and Bretscher et al., 1998). NHERF proteins perform
overlapping functions as regulators of transmembrane receptors, transporters
and other proteins localized at or near the plasma membrane, where ERM
proteins are enriched (Voltz et al.,
2001
). The relationship between NHERF binding and ERM function is
not known.
![]() |
Merlin |
---|
Analysis of the predicted amino acid sequence of merlin reveals three
domains: a FERM domain (residues 1-302), an -helical region (residues
303-478), and a unique C-terminal domain (residues 479-595). The FERM domain
is believed to be responsible for membrane binding in a PtdIns
(4,5)P2-dependent manner
(Hamada et al., 2000
).
Crystallographic analysis of the merlin FERM domain demonstrated similarities
to that of ezrin and moesin (Fig.
2A). However, the merlin FERM domain also contains a seven residue
Blue Box (BB) (residues 177-183, YQMTPEM), which is identical in human and
Drosophila merlin, but not conserved in other ERM proteins
(Shimizu et al., 2002
).
Analysis of the crystal structure of the merlin FERM domain demonstrated the
existence of three well-defined subdomains: A, B and C. Asp70 in the A
subdomain can form a salt bridge with Arg291 and Lys289 in the C subdomain.
Other ERM proteins lack this aspartate residue at this position and are
instead rich in aromatic residues, which effectively pushes the A subdomain
loop away from the C subdomain. These differences in sequence and 3D structure
might be responsible for merlin's unique function as a tumor suppressor and
its distinct protein-protein interactions
(Kang et al., 2002
).
|
Two major isoforms of merlin result from alternative splicing of exon 16.
Isoform 1 is a 595-residue protein encoded by exons 1-15 and 17. Isoform 2
contains exon 16, which inserts 11 unique C-terminal residues followed by a
stop codon that prevents translation of exon 17, generating a 590-residue
protein in which the first 579 residues are identical to isoform 1
(Bianchi et al., 1994). Other
splicing variants have also been identified on the RNA level, but have not
been detected by western blotting. It is not known whether these other
isoforms are expressed under normal physiological conditions or whether they
contribute to merlin function.
In order to function as a tumor suppressor, merlin must form two
intramolecular associations. The first requires the binding of the N-terminus
to the C-terminus, whereas the second involves folding within the N-terminal
domain itself (Fig. 2B). The
association of the N- and C-termini of merlin involves residues 302-308 within
the C subdomain and exon 17 sequences, whereas residues within subdomains A
and C participate in the intra-N-terminus interaction
(Gutmann et al., 1999a;
Sherman et al., 1997
). Merlin
isoform 2 is not capable of head-to-tail self-association
(Sherman et al., 1997
;
Gonzalez-Agosti et al., 1999
).
Folding of the merlin N-terminus is required for the proper localization of
the protein beneath the plasma membrane and influences the interaction between
merlin and actin (Brault et al.,
2001
). However, the merlin N-/C-terminal domain self-association
is relatively weak and dynamic, such that the C-terminus has a relatively
higher affinity for the N-terminus of ezrin than for its own N-terminus
(Nguyen et al., 2001
). The
heteromeric interactions between merlin and ezrin might regulate merlin
function (Meng et al., 2000
),
perhaps by forming complexes that differentially modulate the ability of
merlin to bind to critical effector or regulatory molecules.
![]() |
Merlin in tumorigenesis and development |
---|
In addition to functioning as a negative growth regulator in tumor
formation, the NF2 gene plays an important role in embryogenesis and
tissue differentiation. Complete inactivation of the mouse Nf2 gene
results in embryonic lethality between day 6.5 and day 7.0
(McClatchey et al., 1997).
These mice exhibit a collapsed extraembryonic region and the absence of
organized extraembryonic ectoderm. Similarly, Drosophila merlin is
required in posterior follicle cells to initiate axis formation. Defects in
nuclear migration and mRNA localization in the oocyte are found in
Drosophila merlin mutants
(MacDougall et al., 2001
). In
Drosophila, merlin may additionally regulate cell proliferation
through interactions with another member of the Protein 4.1 family,
expanded (McCartney et al.,
2000
).
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Merlin interacts with the actin cytoskeleton |
---|
In support of an actin cytoskeleton function for merlin,
NF2-deficient schwannoma cells exhibit dramatic alterations in actin
cytoskeleton organization (Pelton et al.,
1998). In these cells, the re-introduction of wild-type, but not
mutant, merlin reverses these abnormalities
(Bashour et al., 2002
). In
addition, regulated overexpression of wild type, but not mutant, merlin in rat
schwannoma cells results in transient alterations in F-actin organization
during cell spreading, abnormalities in cell attachment and reduced cell
motility (Gutmann et al.,
1999b
; Gutmann et al.,
2001a
).
![]() |
Merlin protein interactions |
---|
Paxillin binds to merlin residues 50-70 contained within exon 2 and
facilitates the localization of merlin to the cell membrane where it can
interact with cell surface proteins, such as CD44 and ß1-integrin
(Fernandez-Valle et al., 2002;
Obremski et al., 1998
).
Syntenin is an adaptor protein that couples transmembrane proteoglycans to
cytoskeletal components. Syntenin specifically interacts with merlin isoform 1
(Jannatipour et al., 2001
),
which suggests a possible link between `active' merlin and membrane protein
signaling through the actin cytoskeleton. HRS interacts with merlin both in
vitro and in vivo (Scoles et al.,
2000
). HRS is a 115 kDa tyrosine phosphorylated protein localized
to the cytoplasmic surface of early endosomes and is probably involved in the
regulation of endocytosis and exocytosis
(Clague and Urbe, 2001
;
Hayakawa and Kitamura, 2000
;
Raiborg et al., 2001
;
Urbe et al., 2000
). In
addition, HRS has been suggested to function in the TGFß and EGFR
(epidermal growth factor receptor) signaling pathways
(Chin et al., 2001
;
Miura et al., 2000
). It is
hypothesized that HRS mediates downregulation of EGFR at the cell membrane by
increasing EGFR internalization through an interaction with recruiting sorting
nexin 1 (SNX1) (Clague and Urbe,
2001
). Regulated overexpression of HRS in rat schwannoma cells has
the same consequences as merlin overexpression
(Gutmann et al., 2001b
),
raising the possibility that HRS participates in merlin growth
suppression.
CD44 is a polymorphic transmembrane glycoprotein that functions as a
receptor for hyaluronic acid (Peach et
al., 1993). It is involved in cell adhesion and trafficking as
well as in tumor motility and progression. Merlin interacts in vitro and in
vivo with the cytoplasmic tail of CD44
(Sainio et al., 1997
). CD44
also interacts with several guanine-nucleotide-exchange factors (GEFs) for Rho
family GTPases, such as Tiam-1 (Bourguignon
et al., 2000
) and Vav2
(Bourguignon et al., 2001
). The
interaction of CD44 with these GEFs leads to activation of Rac1 and, under
certain conditions, results in increased Rho activation and altered ERM
protein-plasma membrane associations
(Hirao et al., 1996
). In this
fashion, increased Rho activity could result in phosphorylation of the
C-terminus of ERM proteins to regulate their head-to-tail associations and
function (Matsui et al.,
1998
).
![]() |
Protein 4.1B/DAL-1 |
---|
|
The tumor suppressor function of DAL-1/Protein 4.1B has recently been
documented. Loss of heterozygosity has been found in the chromosome 18p11.3
region where DAL-1 maps in 38% of lung, brain and breast tumors
(Tran et al., 1999). In
addition, the reintroduction of DAL-1/Protein 4.1B into DAL-1-deficient lung
cancer (Tran et al., 1999
) or
meningioma cell lines reduces cell proliferation
(Gutmann et al., 2001c
).
Protein 4.1B loss of heterozygosity (LOH) is a common genetic alteration in
meningiomas, regardless of histological grade, indicating that Protein 4.1B
inactivation might be an early event in meningioma tumorigenesis
(Perry et al., 2000
;
Gutmann et al., 2000
).
However, the ability of Protein 4.1B/DAL-1 to function as a negative growth
regulator is tissue-specific. Although merlin is able to suppress cell
proliferation in schwannoma cells, overexpression of DAL-1 has no effect
(Gutmann et al., 2001c
). This
is consistent with the observation that, in contrast to merlin, Protein 4.1B
expression is not lost in sporadic schwannomas
(Gutmann et al., 2000
).
Although merlin has been shown to interact with several proteins integral
to cell signaling, less is known about Protein 4.1B. To provide insight into
the function of Protein 4.1B/DAL-1, efforts have been made to characterize
potential interacting proteins that might mediate the Protein 4.1B growth
inhibitory signal. Because of the high homology between Protein 4.1 family
members, previously described merlin-binding partners have been assayed for
their ability to interact with DAL-1, the fragment of Protein 4.1B known to
contain the minimal growth suppression domain. In common with merlin, Protein
4.1B/DAL-1 has been shown to interact in vitro with ezrin, radixin and moesin,
as well as with the N-terminus of merlin, possibly reflecting the ability of
all members of the Protein 4.1B family to form intra- and intermolecular
complexes (Gutmann et al.,
2001c). Moreover, Protein 4.1B/DAL-1 also interacts with CD44
(V.A.R. and D.H.G., unpublished) as has been previously reported for Protein
4.1R (Numomura et al., 1997) as well as ßII-spectrin
(Gutmann et al., 2001c
), which
indicates that Protein 4.1B and merlin might signal in a similar manner.
However, Protein 4.1B/DAL-1 does not interact with several known
merlin-interacting proteins, including SCHIP-1
(Gutmann et al., 2001c
).
The demonstration that DAL-1/Protein 4.1B interacts with a subset of
merlin-binding proteins and functions in a cell-type-specific manner raises
the possibility that DAL-1/Protein 4.1B associates with unique proteins that
are specific to its function as a negative growth regulator. Recently, DAL-1
was found to interact with 14-3-3 molecules both in vivo and in vitro
(Yu and Robb et al., 2002),
which are involved in cell cycle regulation (reviewed by
Muslin and Xing, 2000
).
Moreover, this interaction was specific to DAL-1/Protein 4.1B and was not
observed with other Protein 4.1 family members (Yu and Robb, 2002). Since CD44
and 14-3-3 have each been implicated in mitogenic signaling pathways, the
association of Protein 4.1B with these proteins might be important for
transduction of the Protein 4.1B growth inhibitory signal.
![]() |
Other Protein 4.1 growth suppressors |
---|
![]() |
Proposed model of Protein 4.1 molecule growth suppression |
---|
|
In this model, growth permissive conditions enable the activation of small
GTPase molecules, such as Rac and Rho, which results in phosphorylation of ERM
proteins, perhaps on specific C-terminal threonine or serine residues.
Phosphorylated and `unfolded' ERM proteins bind to CD44 in this activated
conformation, leading to cellular remodeling and facilitating cell
proliferation (Matsui et al.,
1998; Matsui et al.,
1999
). Under these growth permissive conditions, merlin is also
phosphorylated, perhaps by Rac1-dependent Pak activation, resulting in an
`open' and `inactive' merlin molecule incapable of negatively regulating cell
growth, but still able to bind ERM proteins
(Morrison et al., 2001
;
Shaw et al., 2001
;
Kissil et al., 2002
;
Xiao et al., 2002
). As ERM
proteins associate with CD44 at low cell density and the merlin C-terminus has
a high affinity for the N-terminus of ezrin
(Nguyen et al., 2001
), this
`open' conformation of ezrin might serve to retain merlin in an `inactive'
state at the plasma membrane under growth-permissive conditions.
In contrast, when cells are stimulated to undergo growth arrest by cell
contact or specific extracellular matrix cues (e.g. high-molecular-weight
hyaluronic acid), merlin and perhaps ERM proteins both exist in
hypophosphorylated states, resulting in molecules in the `closed' conformation
(Morrison et al., 2001). This
would favor binding of merlin to the cytoplasmic tail of CD44 to promote cell
growth suppression (Sherman and Gutmann,
2001
). In this growth inhibitory state, ERM proteins (ezrin) might
not be as tightly associated with CD44
(Morrison et al., 2001
). This
model predicts that the phosphorylation state of merlin is modulated by growth
arrest signals, such as confluency and serum deprivation, with the
hypophosphorylated form being associated with growth arrest
(Shaw et al., 1998
).
On account of the striking sequence similarity among Protein 4.1 family members, it is conceivable that the productive interaction of select Protein 4.1 members (e.g. Protein 4.1B) and transmembrane molecules (e.g. CD44) also transduces their growth inhibitory signals. Based on available data, it is premature to propose a model of growth suppression for all Protein 4.1 growth suppressors. Further study of the complex relationship between growth regulatory members of the Protein 4.1 family and their binding partners will undoubtedly yield important insights into the mechanisms that underlie context-dependent growth arrest. With an improved understanding of the critical protein interactions important for Protein 4.1 molecule growth suppression and the processes that modulate Protein 4.1 molecule activity, it is conceivable that novel and targeted cancer therapies may be developed.
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Footnotes |
---|
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---|
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