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MINIREVIEW
What MAN1 does to the Smads
TGFb/BMP signaling and the nuclear envelope
Luiza Bengtsson
Institute for Chemistry and Biochemistry, Free University Berlin, Germany
Introduction
Our knowledge about the nuclear membrane has
advanced dramatically in the recent years. We now
know that protein residents of the nuclear membrane
regulate processes as diverse as DNA replication and
transcription, control of the shape and stability of the
nucleus, cell cycle progression, chromatin organiza-
tion, cell development and differentiation, nuclear
anchoring and migration, and apoptosis (reviewed in
[1,2]). Mutations in several of the integral membrane
proteins of the inner nuclear membrane (emerin,
MAN1, lamin B receptor) and their common binding
partners (lamins) cause distinct diseases, the molecular
mechanisms of which are not yet understood [1,3,4].
One of the current hypotheses suggests that the
diseases result from altered gene expression in affec-
ted tissues and that integral membrane proteins of
the inner nuclear membrane (INM) regulate gene
expression either directly, or as components of tran-
scription regulating protein complexes [3,5,6]. Indeed,
both emerin and MAN1 bind the transcriptional
repressors germ cell-less (GCL) and Bcl-2-associated
transcription factor (Btf) [7,8]. In addition, loss of
emerin leads to up-regulation of expression of 28
genes, which can be rescued by reintroducing emerin
[9]. LAP2b, another INM protein, can repress trans-

cription by recruiting histone deacetylase [10], or
Keywords
BMP; laminopathy; MAN1; nuclear
envelope; phosphatase; signal transduction;
Smad; TGFb
Correspondence
L. Bengtsson, Institute for Chemistry and
Biochemistry, Free University Berlin,
Thielallee 63 14195 Berlin, Germany
Tel: +49 30 838 54789
E-mail:
Previous address
Department of Cell Biology, Johns Hopkins
University School of Medicine, 725 N. Wolfe
St, Baltimore, MD 21205, USA
(Received 8 March 2006, accepted 8 Janu-
ary 2007)
doi:10.1111/j.1742-4658.2007.05696.x
The inner nuclear membrane protein MAN1 has been identified as an
important factor in transforming growth factor b⁄ bone morphogenic pro-
tein (TGFb ⁄ BMP) signaling. Loss of MAN1 results in three autosomal
dominant diseases in humans; all three characterized by increased bone
density. Xenopus embryos lacking MAN1 develop severe morphological
defects. Both in humans and in Xenopus embryos the defects originate from
deregulation of TGFb ⁄ BMP signaling. Several independent studies have
shown that MAN1 is antagonizing TGFb ⁄ BMP signaling through binding
to regulatory Smads. Here, recent progress in understanding MAN1 func-
tions is summarized and a model for MAN1-dependent regulation of
TGFb ⁄ BMP signaling is proposed.
Abbreviations

BAF, barrier-to-autointegration factor; BMP, bone morphogenic protein; Btf, Bcl-2-associated transcription factor; GCL, germ cell-less;
INM, inner nuclear membrane; LAP, lamina associated polypeptide; MH-domain, Mad homology domain; pRb, retinoblastoma protein;
PP, protein phosphatase; RR-motif, RNA recognition motif; R-Smads, regulatory Smads; SANE, Smad1 antagonistic effector; TGFb,
transforming growth factor b; UHM, U2AF homology motif; WH, winged-helix.
1374 FEBS Journal 274 (2007) 1374–1382 ª 2007 The Author Journal compilation ª 2007 FEBS
through binding to GCL [11]. Lamin A binds the
transcription repressors retinoblastoma protein (pRb)
and MOK2 (reviewed in [1,12]). Finally, the nuclear
envelope protein MAN1, the subject of this review,
has been shown to bind regulatory Smads (R-Smads)
and antagonize the transforming growth factor
b ⁄ bone morphogenic protein (TGFb ⁄ BMP)-induced
signal transduction pathway [13–17].
Who is MAN1?
MAN1 was first discovered as one of the autoantigens
for the autoantibodies from a patient with collagen
vascular disease [18]. MAN1 is an integral membrane
protein of the INM and belongs to the LEM (Lap2-
emerin-MAN1)-domain family of proteins [18,19]. The
LEM domain is a structural motif [20–22] also found
in emerin, lamina associated polypeptide (LAP)2,
Lem2 [23,24], the Drosophila specific proteins otefin
[25] and Bocksbeutel [26], and other as yet uncharac-
terized proteins named Lem3–5 [23]. LEM domains
bind barrier-to-autointegration factor (BAF [8,27–29]),
an essential DNA-binding protein that has been impli-
cated in the organization of chromatin structure [30–
32] and recruitment of nuclear envelope proteins to the
chromosomes during nuclear assembly [33]. The LEM
domain in MAN1, located at the very N-terminus of

this 100 kDa protein ([18], Fig. 1), is highly conserved
with 82% identity between human and Xenopus MAN1
(xMAN1 [14]). In contrast, the N-terminus outside the
LEM domain is only 30% identical between human
and Xenopus MAN1 [14].
The functions of a MAN1 homolog, the Lem2 pro-
tein, might be representative for the functions of the
MAN1 N-terminus. Lem2 is 19% homologous to
MAN1, has an N-terminal LEM domain, two trans-
membrane domains and a conserved C-terminal nucleo-
plasmic domain [24], but is lacking the C-terminal
RNA recognition motif (RR-motif) found in MAN1
(Fig. 1). Thus, structurally, Lem2 appears as a shorter
version of MAN1. Overexpression of Lem2 in mamma-
lian cells does not affect cell viability, but disturbs nuc-
lear organization, which is manifested by protein
bridges containing lamins and BAF connecting nuclei
of cells that have otherwise completed mitosis [24]. In
contrast, knockdown of the Caenorhabditis elegans
ortholog, the Ce-Lem2 (the gene product of C. elegans
lem-2 gene, also known as ‘Ce-MAN1’ [8,24]), is lethal
in 15% of embryos [34]. Interestingly, simultaneous
down-regulation of Ce-Lem2 and Ce-emerin was lethal
in 100% of embryos by the 100-cell stage [34], while
reduction of Ce-emerin had no noticeable effect [35],
suggesting that Ce-Lem2 and Ce-emerin can substitute
for each other to some extent. It is not yet known whe-
ther MAN1 and emerin are redundant, however, func-
tional overlap is likely, because mammalian MAN1
and mammalian emerin do have many common part-

ners (see below).
MAN1 needs lamins in order to localize to the INM
[34,36,37]. The N-terminus and the first transmem-
brane domain of MAN1 are necessary and sufficient
for MAN1 INM localization [13,38]. The N-terminus
of human MAN1 (up to the first transmembrane
domain) binds prelamin A and B1 [8] in vitro, while
the LEM domain alone is sufficient to bind BAF
(Fig. 1; [8]). Prelamin A and BAF are also binding
partners of emerin [39]. Interestingly, the N-terminus
of human MAN1 binds the human emerin itself
(Fig. 1; [8]). Emerin is an integral membrane protein
and localizes to the nuclear envelope [40]. Mutations
in emerin cause Emery–Dreifuss muscular dystrophy
[41]. Although most disease causing mutations result in
loss of emerin, in some cases the mutated emerin is
present at normal levels and is also correctly localized
(reviewed in [39]). Two of such mutations, the deletion
of residues 95–99 and the substitution Q133H, do
affect MAN1 N-terminus binding to emerin: the bind-
ing was abolished when tested in vitro [8]. Given the
possibility that MAN1 overlaps functionally with
emerin, one might assume that MAN1 stabilizes ⁄ regu-
lates emerin’s functions. Thus, loss of emerin binding
to MAN1 N-terminus and ⁄ or loss of the MAN1–emer-
in complex functions could directly contribute to
the Emery–Dreifuss muscular dystrophy disease
mechanism.
The C-terminus of MAN1 (human MAN1 residues
649–911; Fig. 1) is 87% identical between human and

Fig. 1. Map of binding sites on MAN1. Human and Xenopus MAN1
and C. elegans lem2 sequences were retrieved from NCBI data
bank and pairwise aligned to human MAN1 using
CLUSTALW
[8,13,14,16,17,34,69,70]. Gaps between the boxed areas represent
gaps in the alignment that were larger than 10 amino acids.
Domains were either predicted using
SMART [71] or taken from the
NMR structure [44]. Numbers above the sequence mark the first
and last amino acid of each functional domain. WH, Winged helix
domain; UHM, U2AF homology motif; L, LEM domain; 1, first
transmembrane domain; 2, second transmembrane domain; R,
RR-motif. Black thick lines depict the smallest part of MAN1
required to bind each partner [8,13,14,16,44,69].
L. Bengtsson What MAN1 does to the Smads
FEBS Journal 274 (2007) 1374–1382 ª 2007 The Author Journal compilation ª 2007 FEBS 1375
Xenopus [14] and 55% identical between human and
Ciona intestinalis (a simple eukaryote of the chordate
lineage from which all vertebrates originate), implying
an evolutionarily conserved function. The C-terminus
does not localize to the nuclear envelope by itself
[13,14,38], suggesting it has roles other than targeting.
This part of MAN1 indeed binds several regulators of
gene expression, including transcriptional repressors
GCL and Btf and, surprisingly, also binds BAF [8,34].
There is no LEM domain in the MAN1 C-terminus,
however, a different BAF binding motif common to
MAN1 C-terminus, Histone H1 and the transcription
factor cone-rod homeobox (Crx) has been proposed [8].
The residues 801–857 in human MAN1 (655–734 in

xMAN1) comprise an RR-motif (Fig. 1 [8,13–15]). RR-
motifs in other proteins are known to mediate associ-
ation with RNA [42], but can also function as protein–
protein interaction domains [43]. Several studies have
identified the RR-motif in MAN1 as a binding site for
transcription regulators, the R-Smads [14]. A detailed
NMR analysis of human MAN1 C-terminus revealed
the existence of two globular domains: the experiment-
ally confirmed winged-helix (WH) domain comprising
the residues 655–750 and a putative U2 auxillary factor
homology motif (UHM) consisting of residues 782–911
and including the RR-motif [15,44]. Both the WH
domain and the UHM domain adopt a stable a ⁄ b-fold
found in several DNA-interacting transcription factors
[45]. Indeed, a MAN1 fragment consisting of the WH
domain binds DNA with nanomolar affinity and the
binding is further increased by the presence of the
UHM domain [44]. Because the DNA binding site on
MAN1 does not overlap with the Smad binding site, it
seems possible for MAN1 to bind DNA and Smads
simultaneously [44].
MAN1 is essential for early
development and later tissue-specific
functions
MAN1 mRNA is maternally expressed in Xenopus
embryos [14]. By the tailbud stage, the expression of
xMAN1 is restricted to anterior central nervous sys-
tem, eyes, otic vesicles and bronchial arches [14]. Strik-
ingly, xMAN1 expression starts to diminish at stage 34
and is completely down-regulated by stage 45 [14,46].

It is not known whether xMAN1 is expressed in adult
frogs, however, various human cell lines do contain
endogenous MAN1 [13,15], which implies that MAN1
is reactivated in somatic cells. Interestingly, as the
expression of xMAN1 is turned off, expression of both
Xenopus emerin genes is turned on [46], which suggests
yet another link between MAN1 and emerin functions.
Xenopus embryos injected with antisense morpholino
oligos against xMAN1 gastrulated normally [14]. Like-
wise, down-regulation of Drosophila MAN1 by RNAi
does not affect the early development of the embryos
[37]. At later stages however, the Xenopus embryos
showed severe morphological anomalies: their right
eyes were absent or poorly formed [14]. The eye defects
correlated with several target genes of BMP signaling
being up-regulated in the xMAN1 morphants, implica-
ting xMAN1 in BMP signaling [14]. It is not clear
whether treatment with antisense morpholino oligos
against xMAN1 resulted in a true null-phenotype,
because, due to partial tetraploidy there might be
another xMAN1 gene in Xenopus.
In mammalian cells, MAN1 siRNA enhanced
TGFb, activin and BMP signaling, because several
gene targets of these pathways were up-regulated com-
pared to controls [15]. Reduced MAN1 expression also
made the cells more sensitive to TGFb-induced growth
inhibition [15].
Mutations in human MAN1 result in osteopoikilo-
sis, Buschke–Ollendorff syndrome and melorheostosis
[17]. All three disorders are autosomal dominant and

are characterized by increased bone density [47]. In
Buschke–Ollendorff syndrome, the osteopoikilosis is
associated with disseminated connective tissue nevi. In
melorheostosis, the bone hyperostosis is accompanied
by abnormalities of adjacent soft tissues, such as joint
contractures, sclerodermatous skin lesions, muscle
atrophy, hemangiomas and lymphoedema [17]. The
disease causing mutations result in haploinsufficiency
with respect to full-length MAN1 [17]. There are two
possibilities for how the mutations in MAN1 could
cause disease: (a) the mutated protein is specifically
interfering with remaining wildtype MAN1 functions,
and ⁄ or (b) half the amount of MAN1 in cells is not
enough to keep up MAN1 functions. The latter alter-
native is more likely, because overexpression of
mutated proteins in tissue culture cells expressing nor-
mal levels of full-length endogenous MAN1 did not
resemble the MAN1 siRNA phenotype, e.g., TGFb
signaling was not enhanced [17].
TGFb/BMP signaling: the basics
BMP, TGFb and activin belong to a family of pleio-
tropic cytokines. Each cytokine has many different iso-
forms with highly specific functions. These functions
include the context-specific inhibition or stimulation
of cell proliferation, control of extracellular matrix
synthesis and degradation, and the control of epi-
thelial ⁄ mesenchymal interactions during embryogene-
sis. Other functions include wound healing and the
What MAN1 does to the Smads L. Bengtsson
1376 FEBS Journal 274 (2007) 1374–1382 ª 2007 The Author Journal compilation ª 2007 FEBS

modulation of immune functions. Misregulation of
these specific pathways results in developmental disor-
ders, cancer, fibrosis and autoimmune disorders. Signa-
ling is initiated by binding of the cytokine to a
homodimeric complex of cytokine receptor type II,
which recruits type I receptor and activates it by phos-
phorylation. Phosphorylated and thereby activated
type I receptor phosphorylates Smads, which then
form oligomeric complexes and enter the nucleus to
either induce or suppress gene expression by interact-
ing with cell type and signal-specific transcription acti-
vators or repressors. There are three classes of Smads:
regulatory Smads (BMP-responsive R-Smads 1, 5 and
8 and TGFb-responsive R-Smads 2 and 3), the co-
Smad Smad4 and the inhibitory Smads 6 and 7. All
R-Smads and the co-Smad consist of three domains:
the N-terminal MH1 domain, the variable proline-rich
linker, and the C-terminal Mad homology (MH)2
domain. The MH2 domain is highly conserved in
all Smads and is primarily responsible for binding to
different partners in a series of mutually exclusive
protein–protein interactions. The specificity of the
BMP ⁄ TGFb ⁄ activin signal is conferred by mixing and
matching of receptor subtypes in the oligomeric recep-
tor complexes as well as by regulation of Smad interac-
tions in the cytoplasm and in the nucleus. Smads can
be either activated or inhibited by phosphorylation,
sumoylation and ubiquitination (reviewed in [48–54]).
MAN1 antagonizes TGFb/BMP signaling
by binding R-Smads

Xenopus MAN1 was identified as a gene involved in
neuralization and neural patterning during Xenopus
development [14]. The RR-motif in MAN1 was neces-
sary but not sufficient for the neuralizing activity,
while neither the LEM domain nor the whole N-termi-
nus of MAN1 showed any activity [14]. Furthermore,
both full-length MAN1 [16] and the C-terminus alone
[14,16] could induce a partial secondary axis formation
in Xenopus embryos [14]. Both the neuralizing activity
and the secondary axis induction indicate inhibited
BMP signaling. An independent study also discovered
xMAN1 as a negative regulator of the BMP signaling,
but named the protein ‘SANE’ (Smad1 antagonistic
effector) [13]. The cDNA sequences of SANE and
xMAN1 in the NCBI gene database are identical
(gi|56849616 and gi|29335751, respectively) and are
orthologous to human MAN1.
The C-terminus of human MAN1 interacted with
Smads 2 and 3 in a yeast two-hybrid skeletal muscle
library [15]. Additionally, in an affinity-purification of
Smad3 interacting proteins from TGFb-responsive
Hep3B (human liver carcinoma) and RIE-1 (rat intest-
inal epithelial) cells, MAN1 was among the proteins
that bound specifically [15]. Various independent meth-
ods ranging from in vivo coimmunoprecipitation to
direct in vitro binding assays confirmed the direct inter-
action between MAN1 and all regulatory Smads
(BMP and TGFb-responsive) but not the co-Smad or
the inhibitory Smads [13–17]. The interaction was
mapped to the RR-motif in MAN1 and the MH2

domain of R-Smads (Fig. 1; [14,16]). RNAse treatment
had no effect on the MAN1 ⁄ Smad binding suggesting
that the RR-motif in MAN1 is a protein–protein inter-
action domain [13–17].
Several independent experiments suggest that the
antagonizing activity of MAN1 in TGFb ⁄ BMP signa-
ling depends on its ability to bind R-Smads. When tes-
ted using luciferase reporters containing response
elements from the BMP-responsive gene Xvent2, both
full-length xMAN1 and the C-terminus alone inhibited
luciferase gene expression after BMP4 stimulation,
while the N-terminus alone had no effect [16].
Although TGFb and activin signaling were unaffected
by MAN1 overexpression in Xenopus embryos
[13,15,17], in mammalian cell lines both the full-length
MAN1 [13] and its C-terminus alone [15,17] were cap-
able of antagonizing TGFb-, BMP- and activin-signa-
ling. Similarly, human MAN1 with mutated RR-motif
was defective in antagonizing both BMP and TGFb
signaling in tissue culture cells [15].
MAN1 does not bind inhibitory Smads or the
co-Smad [15]. Moreover, MAN1 does not bind R-
Smad–co-Smad complexes [15]. The association of
MAN1 with R-Smads is not regulated by the signaling
pathway, because neither stimulation with TGFb or
BMP, nor overexpression of constitutively active type I
receptor for TGFb, BMP or activin increases the
amount of R-Smad bound to MAN1 [15]. MAN1
binds both phosphorylated and unphosphorylated
R-Smads [15]. At the same time, overexpression of

MAN1 lowers the cellular pool of phosphorylated R-
Smads [15,16] and prevents accumulation of R-Smads
in the nucleus after cytokine-induced activation [15].
Importantly, the R-Smads are not being degraded as a
result of MAN1 overexpression (shown for Smad3
[13], Smad2 [16] and xSmad1 [16]).
The model: MAN1 disrupts the
R-Smad–co-Smad complexes and
promotes dephosphorylation of
R-Smads
How can MAN1 attenuate TGFb ⁄ BMP signaling by
binding R-Smads? As an INM protein and not a part
L. Bengtsson What MAN1 does to the Smads
FEBS Journal 274 (2007) 1374–1382 ª 2007 The Author Journal compilation ª 2007 FEBS 1377
of the nuclear pore complexes, MAN1 is unlikely to
block Smad entry into the nucleus. It is also unlikely
that MAN1 simply sequesters R-Smads at the nuclear
envelope and thus prevents transcription from their
target genes [15,36,55] – this would result in an accu-
mulation of the R-Smads at the nuclear periphery and
not in the observed cytoplasmic accumulation [15].
MAN1 is predicted to be able to bind DNA and
R-Smads simultaneously [44], thus it may assist in acti-
vation or repression of TGFb ⁄ BMP target genes at the
nuclear envelope. It is formally possible that such
genes code for antagonists of TGFb ⁄ BMP signaling
and their expression results in overall signal attenu-
ation. However, effects on Smad phosphorylation and
Smad nuclear localization were studied after 1 h of
TGFb1 stimulation [15] implicating that the antagon-

izing mechanism is more direct.
Smad-mediated signaling has two important proper-
ties: (a) only phosphorylated complexed R-Smads are
retained in the nucleus, and (b) only phosphorylated
R-Smads in complex with the co-Smad can initiate or
inhibit transcription of TGFb ⁄ BMP target genes
[48–54,56]. Thus MAN1 has to either disrupt R-Smad–
co-Smad complexes and ⁄ or induce dephosphorylation
of R-Smads in order to attenuate the Smad-mediated
signal. This hypothesis is supported by several experi-
mental data: (a) it has been shown that MAN1 bound
Smad3 is not associated with the co-Smad, in contrast
to ‘free’ Smad3 [15]; (b) overabundance of MAN1 cor-
relates with lower cellular pool of phosphorylated
Smads [16]; (c) upon overexpression of MAN1
R-Smads do not accumulate in the nucleus, indicating
lost retention in the nucleus and accelerated nuclear
export [14–16], and (d) full-length MAN1 antagonizes
TGFb ⁄ BMP signaling more effectively than the C-ter-
minus alone, implying that the correct nuclear envel-
ope localization of MAN1 is beneficial, but not
necessary for MAN1 functions in TGFb ⁄ BMP signa-
ling [14]. Taken together the data suggests a role for
MAN1 similar to that of the inhibitory Smad 6. Smad
6 inhibits TGFb ⁄ BMP signaling not only by binding
the respective type I receptors and interfering with
phosphorylation of Smads, but also by binding
R-Smads and preventing them from heterooligomeriz-
ing with co-Smad and forming active complexes
(reviewed in [57]). Hypothetically, MAN1 may be act-

ing as a ‘molecular filter’, catching a portion of the
Smad complexes that enter the nucleus and forcing the
complexes apart by binding the R-Smad and displacing
the co-Smad. Monomeric Smads would become rap-
idly dephosphorylated and exported out of the nucleus.
MAN1 may also recruit a nuclear phosphatase to
dephosphorylate Smads and reinforce Smad complex
disassembly. Two nuclear Smad phosphatases have
recently been identified: pyruvate dehydrogenase phos-
phatase (PDP) for BMP responsive R-Smads [58] and
PPM1A for TGFb responsive R-Smads [59]; both are
members of the metal-ion-dependent protein phospha-
tase family and both are distributed throughout the
nucleus. Two further phosphatases, the protein phos-
phatase 1 (PP1) and the protein phosphatase 2 A
(PP2A) are anchored at the nuclear periphery [60–62].
Overexpression of the catalytic domains of PP1 and
PP2A did not have any effect on Smad phosphoryla-
tion [58,59]; however, both phosphatases need a regu-
latory subunit in order to find their targets [63]. PP1 is
responsible for dephosphorylating lamins throughout
the interphase, while PP2A dephosphorylates pRb in a
cell cycle and lamin dependent manner [60–62]. More-
over, inhibition of PP2A increases the phospho-Smad
pool in the cells only when lamins are present. Thus,
both PP1 and PP2A are potentially in the right place
to dephosphorylate MAN1-bound Smads. The pro-
posed model is summarized in Fig. 2.
Why MAN1?
Any inhibition of BMP ⁄ TGFb signaling by MAN1

has to be a strictly local process restricted to the nuc-
lear envelope. Why is it important to have a signaling
antagonist posted there? MAN1 can potentially bind
both DNA and R-Smads and is therefore able to influ-
ence gene expression directly [44]. It is not yet known
which exact genes are under transcriptional control by
MAN1, but the fact that haploinsufficiency of MAN1
causes severe bone disorders [17] suggests that the
genes in question are central for cell functions and
have to be tightly regulated. Thus MAN1 would hypo-
thetically both transduce the Smad-mediated signal
and attenuate it at the same time. Alternatively,
MAN1 might be safeguarding the nuclear periphery
against concentration of active Smad complexes which
could potentially interact with other INM proteins and
the lamina and negatively influence regulation of gene
expression [2].
Could emerin be involved?
At least in C. elegans embryos, Ce-emerin seems to
provide a backup mechanism for functions of the
MAN1 homolog Ce-lem2 [34]. In Xenopus embryos
emerin gene expression begins as MAN1 expression
diminishes [46]. In somatic human cells, both emerin
and MAN1 are expressed [17,18,39]. Human emerin
and human MAN1 have many common binding part-
ners [8,39], but it is not yet known if emerin also binds
What MAN1 does to the Smads L. Bengtsson
1378 FEBS Journal 274 (2007) 1374–1382 ª 2007 The Author Journal compilation ª 2007 FEBS
Smads. Emerin binds the N-terminus of MAN1 [8] and
has thus the potential to regulate the TGFb ⁄ BMP sign-

aling antagonizing activity of MAN1. Emerin is
retained at the nuclear membrane by lamins (reviewed
in [39]) and Nesprin 2 [64,65]. Interestingly, the expres-
sion of synaptic nuclear envelope-2, a short isoform of
the giant Nesprin 2 [64–66] also located at the nuclear
membrane, is specifically up-regulated in response to
TGFb signal [67,68]. If nesprins serve as scaffolds for
protein complexes containing MAN1, emerin, lamins,
protein phosphatases and other components, then the
up-regulation of nesprin expression might function as a
feedback mechanism. In such a feedback mechanism,
the cytokine signal results in translocation of phos-
phorylated Smads into the nucleus, leading to higher
expression of nesprins. More nesprins could then hypo-
thetically link more emerin ⁄ phosphatases ⁄ MAN1 pro-
tein complexes which would eventually lead to
enhanced dephosphorylation of Smads and attenu-
ated ⁄ terminated signal.
The discovery that the INM protein MAN1 binds
Smads and antagonizes cytokine signaling also raises
the question what roles other nuclear envelope proteins
might have in cellular signal transduction. We know
that several of them (LAP2b, emerin, lamin A) can
regulate gene expression [1,9,11,12]; future studies will
have to tell whether they do it on orders coming from
the plasma membrane.
Acknowledgements
The first version of this review was written while I was
a postdoctoral fellow in Katherine L. Wilson’s lab
(spring 2005). Warmest thanks to Katherine L. Wilson

and members of the Wilson lab, especially K. E. Tifft,
M. Mansharamani and M. S. Zastrow for comments
on the manuscript, to R. Schwappacher for fruitful
discussions and to Petra Knaus for her support. LB
was funded by a postdoctoral fellowship from the
Deutsche Forschungsgemeinschaft.
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