Signalling pathways and the regulation of SUMO conjugation

Abstract

The modification of proteins by SUMO (small ubiquitin-related modifier) conjugation is becoming increasingly recognized as an important regulatory event. Protein SUMOylation can control a whole range of activities, including subcellular localization, protein-protein interactions and enzymatic activity. However, the SUMOylation process can itself be controlled. In the present review, the mechanisms through which protein SUMOylation is regulated are discussed, with particular emphasis on the impact of signalling pathways. A major point of regulation of the SUMO pathway is through targeting the E3 ligases, and a number of different ways to achieve this have been identified. More generally, the MAPK (mitogen-activated protein kinase) pathways represent one way through which SUMOylation of specific proteins is controlled, by using molecular mechanisms that at least in part also function by modifying the activity of SUMO E3 ligases. Further intricacies in signalling pathway interactions are hinted at through the growing number of examples of cross-talk between different post-translational modifications and SUMO modification.

Full text

1414 Biochemical Society Transactions (2007) Volume 35, part 6
Signalling pathways and the regulation of SUMO
modification
B. Guo*, S.-H. Yang*, J. Witty* and A.D. Sharrocks*
1
*Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, U.K.
Abstract
The modification of proteins by SUMO (small ubiquitin-related modifier) conjugation is becoming increasingly
recognized as an important regulatory event. Protein SUMOylation can control a whole range of activities,
including subcellular localization, protein–protein interactions and enzymatic activity. However, the
SUMOylation process can itself be controlled. In the present review, the mechanisms through which protein
SUMOylation is regulated are discussed, with particular emphasis on the impact of signalling pathways.
A major point of regulation of the SUMO pathway is through targeting the E3 ligases, and a number of
different ways to achieve this have been identified. More generally, the MAPK (mitogen-activated protein
kinase) pathways represent one way through which SUMOylation of specific proteins is controlled, by using
molecular mechanisms that at least in part also function by modifying the activity of SUMO E3 ligases.
Further intricacies in signalling pathway interactions are hinted at through the growing number of examples
of cross-talk between different post-translational modifications and SUMO modification.
Introduction
The SUMO (small ubiquitin-related modifier) modification
pathway shows many parallels with the ubiquitin pathway.
Indeed, many of the pathway components show structural
and functional homology (reviewed in [1,2]). This is
illustrated by the fact that SUMO itself is a small polypeptide
that is structurally related to ubiquitin. The SUMO
pathway contains three main enzymatic components,
the E1 activating enzyme [SAE (SUMO1-activating
enzyme) 1/SAE2 also named Aos1/Uba2 (ubiquitin-
activating enzyme 2)], the E2-conjugating enzyme Ubc9
(ubiquitin-conjugating enzyme 9) and a number of E3
ligases that can facilitate the SUMOylation process in a
substrate-specific manner (Figure 1). SUMOylation can
be reversed through the proteolytic action of members
of the SENP [sentrin (also known as SUMO)-specific
protease] family. SUMOylation takes place on lysine
residues that are usually embedded within the core
consensus motif KXE [3]. However, other more exten-
ded motifs have been proposed, including the synergy control
motif [4] (characterized by proline residues in the flanking
regions) and the NDSM (negatively charged amino acid-
Key words: E3 ligase, mitogen-activated protein kinase (MAPK) pathway, protein inhibitor of
activated STAT (PIAS), phosphorylation-dependent SUMOylation motif (PDSM), small ubiquitin-
related modifier (SUMO), SUMOylation.
Abbreviations used: AIB1, amplified in breast cancer 1; CDK, cyclin-dependent kinase;
ERK, extracellular-signal-regulated kinase; ETS, E twenty-six; Elk-1, ETS-like kinase 1; HIC-1,
hypermethylated in cancer 1; HIPK2, homeodomain-interacting protein kinase 2; IκB, inhibitor
of nuclear factor κ B; IKKα,IκBkinaseα; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated
protein kinase; MEK-1, MAPK/ERK kinase 1; MEF2, myocyte enhancer factor 2; NDSM, negatively
charged amino acid-dependent SUMOylation motif; NF-κB, nuclear factor κB; NEMO, NF-κB
essential modulator; PEA3, polyoma enhancer activator 3; SAE, SUMO1-activating enzyme; STAT,
signal transducer and activator of transcription; PIAS, protein inhibitor of activated STAT; SUMO,
small ubiquitin-related modifier; PDSM, phosphorylation-dependent SUMO modification; RanBP2,
Ran-binding protein 2; Ubc9, ubiquitin-conjugating enzyme 9.
1
To whom correspondence should be addressed (email a.d.sharrocks@manchester.ac.uk).
dependent SUMOylation motif) (characterized by clusters
of acidic residues in the downstream region) [5]. These
extended motifs provide further specificity and enhanced
intrinsic propensities for SUMOylation. Further variations
on these motifs can impart regulatory properties (see below).
However, while most of the substrates contain the core
KXE motif, a significant number do not, and in those cases,
other structural constraints are thought to be important.
The functions attributed to SUMO modification differ
significantly from those identified for ubiquitin, which
predominantly targets proteins for degradation. Indeed,
SUMO modification has been shown to exhibit a number
of disparate functions depending on the protein substrates
(reviewed in [1,2,6]). One of the major roles emerging for
SUMOylation is in controlling the output from transcrip-
tional regulatory proteins, and in particular in mediating
transcriptional repression (reviewed in [7]). However, roles
in recombination, DNA repair and a growing number of
cytoplasmic processes have been uncovered (reviewed in [ 6]).
Protein SUMOylation is not a static process. Indeed
SUMOylation appears very dynamic, with typically only a
small proportion of any protein being modified. The latter
observation has been suggested to equate to a role of SUMO
in establishing a particular state that is then maintained
through the action of other proteins and/or modifications
(reviewed in [1]). Dynamic SUMOylation is observed in
many situations, but is clearly demonstrated during circadian
clock control where cyclical SUMOylation of BMAL1
(brain and muscle Arnt-like protein-1) parallels its rhythmic
activation [8]. A number of ways of regulating protein
SUMOylation have been discovered (reviewed in [9]). Here,
we describe some of the latest advances in this area, with a
particular focus on the role of signalling pathways in the regu-
lation of E3 ligases and the role of MAPK (mitogen-activated
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Regulation of Protein Function by SUMO Modification 1415
Figure 1 The SUMO pathway and points of regulation
Components of the SUMO pathway are shown as ovals, and a putative
substrate as a rectangle. Only one E1 (SAE1/SAE2) and one E2 (Ubc9)
enzyme exist but there are multiple potential E3 ligases. Three possible
points of regulation of the pathway are shown: through inactivating the
E1 SUMO activating enzyme (I), inactivating the E2 SUMO conjugating
enzyme (II), or changing the activity of the E3 ligases (III) (see the text
for details).
protein kinase) pathways in controlling protein SUMOy-
lation status.
Global mechanisms for SUMOylation
control
Protein SUMOylation can be regulated in a substrate-specific
manner (see below) or in a more global way. Typically,
global SUMOylation is controlled by targeting one of the
core SUMO pathway components. However, control exerted
over the whole pathway has also been observed. For example,
studies in keratinocytes demonstrated that the whole SUMO
pathway is transiently up-regulated during differentiation,
thereby causing changes in the global patterns of protein
SUMOylation [10]. It is also well documented that various
stress stimuli cause changes in global SUMOylation patterns
(reviewed in [9]). For example, various cellular stresses,
including heat shock, cause global increases in SUMOylation
in mammalian cells [11]. Conversely, reductions in global
SUMOylation levels can be seen and one way this is achieved
is through targeting the E2 enzyme Ubc9. Low doses of H
2
O
2
cause the reversible oxidation of the E2-conjugating enzyme
Ubc9 [12]. This oxidation event inactivates Ubc9 and causes
a global decrease in SUMOylation levels. Similar reductions
in global SUMOylation levels are seen upon infection with
the CELO (chicken embryo lethal orphan) adenovirus, and
this effect can be attributed to the Gam1 protein, which tar-
gets the E1 activating enzyme SAE1/SAE2 and the E2 Ubc9
for destruction [13]. In the case of viral infection, the loss of
SUMOylation is thought to benefit the virus due to the result-
ing de-repression of many transcriptional processes, thereby
providing a permissive environment for viral propagation.
MAPK pathways and regulation of
SUMOylation
One way in which SUMOylation can be controlled is
through the action of protein kinase cascades in response to
extracellular signals. In particular, such cascades potentially
provide specificity to controlling the SUMOylation of a
limited number of substrates under defined conditions.
The MAPK pathways are a common route through
which extracellular signals are transduced into intracellular
responses (reviewed in [14]). Different pathways can
transduce stress [JNK (c-Jun N-terminal kinase) and p38
pathways] or mitogenic [ERK (extracellular-signal-regulated
kinase) pathway] signals. A direct link between these
pathways and SUMOylation was first demonstrated by
the observation that activation of the ERK pathway caused
de-SUMOylation of the transcription factor Elk-1 [ETS
(E twenty-six)-like kinase 1] [15]. As SUMOylation levels
decrease, Elk-1 phosphorylation increases and permits Elk-1
to go from a transcriptionally repressive to a transcriptionally
active form. However, the link between MAPK activation
and Elk-1 de-SUMOylation remains obscure. More recently,
the E3 ligase PIAS [protein inhibitor of activated STAT
(signal transducer and activator of transcription)] xα has
been implicated in controlling this switch but appears to do
so independently of its SUMO ligase activity [16].
A growing number of links are now being made between
the MAPK pathways and protein SUMOylation. For
example, treatment of cells with 17β-oestradiol causes
up-regulation of the ERK MAPK pathway and enhanced
phosphorylation of the co-activator protein AIB1 (amplified
in breast cancer 1) {also known as RAC3 (receptor-associated
co-activator 3), ACTR (activator of thyroid and retinoic
acid receptors), SRC-3 (steroid receptor co-activator 3)
and p/CIP [p300/CBP (cAMP-response-element-binding
protein-binding protein)]}. This phosphorylation inversely
correlates with AIB1 SUMOylation, and mutational analysis
suggests mutual cross-regulation of phosphorylation and
SUMOylation [17]. It is however unclear how this occurs at
the molecular level as the SUMOylation sites are not close
to the phosphorylation sites in the primary sequence.
In contrast with the role of MAPK pathways in promoting
de-SUMOylation, it is also feasible that they might also
promote SUMOylation under some circumstances. Indeed,
recently, we have studied the role of ERK MAPK signalling
in potentially controlling SUMOylation of the ETS-
domain transcription factor PEA3 (polyoma enhancer
activator 3) and found that ERK signalling promotes PEA3
SUMOylation (B. Guo and A.D. Sharrocks, unpublished
work). Furthermore, SUMOylation appears to promote
transcriptional activation by PEA3; thus ERK signalling can
enhance the transactivation capacity of different ETS-domain
transcription factors through modifying their SUMOylation
status in an opposite manner (Figure 2). In the case of
Elk-1, loss of repressive SUMO enhances transactivation,
but for PEA3, increases in activating SUMO modifications
cause the same molecular effect, thereby providing two
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1416 Biochemical Society Transactions (2007) Volume 35, part 6
Figure 2 MAPK-mediated control of SUMOylation
SUMOylation of transcription factors (TF) can enhance their repressive
activities (left) or increase their transactivation capacity (right). MAPKs
can potentially enhance the transactivation properties of transcription
factors through two diametrically opposed mechanisms: reduction of
SUMOylation levels (as observed for Elk-1 [15]) or increased SUMOylation
levels (as observed for PEA3; B. Guo and A.D. Sharrocks, unpublished
work).
different modes of regulatory logic to reach the same
endpoint.
Intriguingly, one of the first suggestions of a link between
MAPK signalling and the regulation of SUMOylation was
the observation that p38 signalling led to the increased
Smad4 SUMOylation [18]. T his increase in SUMOylation
was thought to be due to the up-regulation of the SUMO
E3 ligase PIASxβ at the transcriptional and protein levels.
In addition to increasing the levels of PIASx proteins, p38
signalling has also been directly implicated in modifying the
activity of these proteins [19]. These additional links between
the p38 pathway and E3 ligases were made during a study
of the effect of stress signalling on Elk-1 SUMOylation
levels. Whereas mitogenic signalling via the ERK MAPK
pathway causes de-SUMOylation, stress signalling via the
p38 pathway does not cause de-SUMOylation although
Elk-1 still becomes phosphorylated [19]. Interestingly, the
E3 ligase PIASxα plays a key role in both cases. Whereas
PIASxα promotes de-SUMOylation in response to ERK
pathway signalling, PIASxα is required to maintain Elk-1
SUMOylation upon p38 pathway activation. The switch
between these two modes of operation is through p38-
mediated phosphorylation of PIASxα. Thus PIASxα acts
as a molecular rheostat that controls the transcriptional
activation output from Elk-1 by either facilitating loss or
promoting retention of the repressive SUMO modification,
depending on the pathway that is activated.
Thus a common theme seems to be the involvement of
E3 ligases in controlling SUMOylation in the response to
signalling pathway activation.
E3 ligases as a focal point for regulation?
Unlike the ubiquitin pathway where multiple E2 proteins
exist, there is only a single E2 ligase in the SUMO pathway.
Thus any regulation of Ubc9 is likely to produce a global
response, as illustrated in the case of regulating Ubc9 activity
by H
2
O
2
[12]. Thus the E3 ligases represent an attractive
point for potential regulation. It is currently unclear
how many E3 ligases exist, but to date several have been
identified including PIASxα, PIASxβ, PIAS1, PIAS3, PIASy,
RanBP2 (Ran-binding protein 2), Pc2 and HDAC4 (histone
deacetylase 4) (reviewed in [1,20]). Several recent studies
have implicated these proteins as points for regulation.
NEMO (NF-κB essential modulator) is a regulator of
NF-κB (nuclear factor κB) activity, and NEMO itself is
SUMOylated in response to genotoxic agents, which in turn
leads to NF-κB activation. Recently, PIASy was identified
as the SUMO E3 ligase for NEMO, and genotoxic stress
promotes the interaction of NEMO and PIASy [21]. Thus an
important regulated interaction between a substrate and
an E3 ligase h as been defined, although it is currently unclear
how genotoxic stresses promote this interaction.
Another E3 ligase Pc2 has also been shown to be regulated
in response to DNA-damaging agents [22]. In this case,
direct molecular links have been established whereby HIPK2
(homeodomain-interacting protein kinase 2) is activated
following DNA damage, and this then phosphorylates
Pc2. The E3 ligase activity of phosphorylated Pc2 is
enhanced and one target is HIPK2 itself, and SUMOylation
promotes the ability of HIPK2 to act as a transcriptional
repressor. This provides a nice example of a feedback loop
where mutual regulatory modifications (SUMOylation and
phosphorylation) are exchanged between Pc2 and HIPK2.
Further interactions between signalling pathways and E3
ligases have been made with PIAS1, which is a direct target of
IKKα [IκB (inhibitor of NF-κB) kinase α] following expos-
ure of cells to pro-inflammatory stimuli [23]. Phosphoryl-
ation of PIAS1 promotes its ability to associate with pro-
moters and reduce the binding of other transcription factors
including STAT1 and NF-κB. Complex interactions between
SUMOylation and phosphorylation are suggested by the
observation that the E3 ligase activity of PIAS1 is needed
for phosphorylation by IKKα. However, the intrinsic ligase
activity of PIAS1 is not affected by phosphorylation. This
has several parallels with the Elk-1–PIASx interaction where
the SUMO E3 ligase is a target of a stress-activated signalling
pathway and the functional output is in promoting or inhib-
iting other binding events at the promoter rather than being
dependent on global changes in the E3 ligase activity [19].
A third class of E3 ligase, RanBP2, is also subject to
regulatory phosphorylation. In this case, CDKs (cyclin-
dependent kinases) act upon RanBP2 during the cell cycle,
but the functional consequences of this phosphorylation
event are currently unknown [24]. Furthermore, signalling
through the PKB (protein kinase B; also called Akt) pathway
leads to up-regulation of RanBP2 levels [25], suggesting that
RanBP2 is also subject to regulation at multiple levels.
Cross-talk between SUMO and other
post-translational modifications
SUMOylation takes place on lysine residues, which can
also be modified by other post-translational modifications,
including acetylation, methylation and ubiquitination.
This provides ample opportunity for regulatory cross-talk
between different pathways that culminate in different
modification events. Indeed several early studies on the
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Regulation of Protein Function by SUMO Modification 1417
SUMO pathway highlighted the direct antagonism that exists
for SUMOylation and ubiquitination of the same residues
in IκBα [26]. Similarly, in PCNA (proliferating-cell nuclear
antigen), dynamic switching between SUMOylation and
ubiquitination of the same residues has been observed [27].
More recently, acetylation has been shown to antagonize
SUMOylation of the s ame lysine residues in substrates such
as MEF2 (myocyte enhancer factor 2) [20,28] and HIC-1
(hypermethylated in cancer 1) [29]. Moreover, in the case
of MEF2, phosphorylation appears to be a direct trigger
that permits switching between acetylated and SUMOylated
states [28]. Phosphorylation of MEF2 takes place on a serine
residue located three amino acids downstream from the
core SUMOylation motif, and phosphorylation promotes
SUMOylation [28,30,31]. The kinase thought to be involved
in this switch is CDK5, which recognizes the core SP motif
[30], and phosphorylation is reversed by the phosphatase
calcineurin [28]. A similar phosphorylation-dependent
switch controlling SUMOylation levels was also identified in
HSF-1 (heat-shock factor 1) [32] and led to the identification
of a panel of potential SUMO substrates that contain
this extended motif, KXEXXSP, and was named the
PDSM (phosphorylation-dependent SUMOylation motif)
(reviewed in [33]). Importantly, this motif is related to the
NDSM, as it appears that it is the negative charge imparted
by the phosphorylation event that is a key determinant
in enhancing substrate SUMOylation. Thus two types of
substrates can be identified in which SUMOylation is
constitutively enhanced due to the presence of an NDSM, or
inducibly controlled through the PDSM. A further variation
on this theme was suggested from work on HIC-1, where
the proline residues in the core motif, KXEP, were shown
to be important in controlling the acetylation–SUMOylation
switch on the lysine residue [29]. Thus different extended
SUMO motifs impart different regulatory potential to
the SUMOylation process.
The above examples therefore illustrate the potential
for regulatory cross-talk between different pathways and,
in the case of MEF2, direct links to cellular signalling
pathways have been made whereby these pathways control
substrate SUMOylation through controlling substrate
phosphorylation levels.
Perspectives
Our current view of SUMOylation is evolving from one
in which SUMO is a static modification or one that is
cycled as a default mechanism to one where, in many
cases, substrate SUMOylation is controlled by signalling
pathways. This control can be exerted directly through
phosphorylation-dependent switches on the substrate or
indirectly through control of the SUMO pathway itself. One
key area for regulation appears to be through the E3 ligases,
but equally regulation might occur at the level of the SUMO
proteases and this is likely to be an area for future studies.
The MAPK pathways have been linked to controlling
protein SUMOylation of several substrates, and it is tempting
to speculate that in some cases, novel direct regulatory links
will be made through the PDSM, KXEXXSP, as the SP
motif corresponds to the consensus site for this class of
kinase. Reciprocally, links between the SUMO pathway and
MAPK pathway activity can be envisaged as demonstrated
by the stimulatory effect that PIAS1 has on the JNK MAPK
pathway [34].
More recent discoveries such as the observation that
the protein tyrosine phosphatase PTP1B is regulated by
SUMOylation [35] suggest even more complex reciprocal
links between SUMOylation and signalling pathways.
Indeed, previous studies have demonstrated that the MAPK
pathway component MEK-1 (MAPK/ERK kinase 1) is
SUMOylated in Dictyostelium and t his SUMOylation
event is also regulated by MEK-1 phosphorylation by
upstream kinases [36]. In addition to classical signalling
pathways, nuclear hormone receptors can also influence
the output of signalling cascades by transrepression activity
at promoters. Ligand-dependent SUMOylation of nuclear
hormone receptors LXR (liver X receptor) and PPARγ
(peroxisome-proliferator-activated receptor γ ) enhances
their transrepressive properties and inhibits the expression of
genes that are usually responsive to inflammatory signalling
[37,38]. Thus, depending on the inflammatory signals
and nuclear hormone ligands present, then ultimately the
SUMOylation levels of nuclear hormone receptors control
the overall transcriptional response of the cell.
Future studies will undoubtedly uncover more intricacies
in the links between intracellular signalling pathways and
SUMOylation control. Potentially, these links may identify
important areas that could be targeted for therapeutic
intervention in diseases such as cancer where signalling
pathway wiring is often disrupted.
We apologize to our colleagues whose primary work was not
cited due to space constraints. The work in our laboratory on
protein SUMOylation is supported by the BBSRC (Biotechnology and
Biological Sciences Research Council), the Wellcome Trust and a
Royal Society-Wolfson award to A.D.S.
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doi:10.1042/BST0351414
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