ARTICLE
Auteur(s) : Delphine Lavens, Julie Piessevaux, Jan Tavernier
Department of Medical Protein Research, Faculty of Medicine and
Health Sciences, Flanders Interuniversity Institute for
Biotechnology, VIB09, Ghent University, A. Baertsoenkaai 3, B-9000
Ghent
Tel.: (+00 32) 9 264 93 02; fax: (+00 32) 9 264 94 92
accepté le 8 Septembre 2006
Leptin plays a major role in the regulation of energy homeostasis
and food intake. It is mainly produced in white adipose tissue and,
to a lesser degree, in the stomach and in some other tissues [1,
2]. Leptin is released into the circulation and is translocated
through the blood-brain-barrier (BBB) to target the leptin receptor
(LR) in the hypothalamus. Functioning as an adipostat, it signals
the state of body fat reserves to the brain. Aberrations in leptin
signalling are often associated with obesity, but only a minority
of obese individuals show a deficiency in leptin or its receptor.
Instead, most cases of human obesity show a state of relative
leptin resistance, as reflected in high serum leptin levels [3, 4].
This resistance may be situated at different levels in the leptin
pathway, including saturation of transport through the blood-brain
barrier, aberrations in LR signal transduction or downstream
effects on neural networks in the hypothalamus [5, 6].Leptin is a
pleiotropic cytokine. Apart from its role in energy homeostasis, it
is also implicated in a range of other, often peripheral processes,
including immune response, bone formation, angiogenesis and
reproduction. Recent findings suggest that leptin is involved in a
variety of pathological processes, including cardiovascular and
autoimmune diseases [7, 8].Given leptin’s wide range of important
functions, its activities must be under stringent control. In this
review we discuss the molecular mechanisms that are responsible for
the modulation of signal transduction via the LR. A schematic
representation of LR signalling and modulation is shown in ( figure 1 ).
JAK-STAT signalling
At least 5 different LR isoforms exist, but the main player
responsible for signal transduction is the long isoform of the LR
[9]. Canonical leptin signalling occurs through the JAK-STAT
pathway. Ligand binding results in LR clustering, bringing the
associated JAKs (janus kinase) into close proximity. This allows
them to activate each other by cross-phosphorylating tyrosines in
their activation loop. These activated JAK kinases then
phosphorylate tyrosines in the cytoplasmic tail of the receptor and
on the JAKs, forming docking sites for signalling proteins. Amongst
these, the STATs (signal transducers and activators of
transcription) associate with the phosphotyrosines in the receptor
via their SH2 domain and become activated by JAK2 mediated tyrosine
phosphorylation. The activated STATs then dissociate from the
receptor and translocate to the nucleus as dimers to induce
specific target genes.
JAK2 is constitutively associated with the membrane proximal
box1 in the cytoplasmatic tail of the LR [10, 11]. The
intracellular part of the receptor also carries three conserved
tyrosines at positions Y985, Y1077 and Y1138 (murine numbering).
The membrane distal tyrosine is embedded in a YXXQ motif and is
responsible for the recruitment of STAT3 [12, 13]. STAT3 activation
was demonstrated after leptin stimulation in the hypothalamus of
mice [14]. Knock-in mice containing an Y1138S mutation are
incapable of STAT3 activation and reveal a severely obese
phenotype. They do not show the infertility and reduced size that
is seen in db/db mice that are truncated in the long LR, indicative
of the involvement of other signal transducers [15]. Leptin-induced
activation of STAT1 and STAT5B, in addition to STAT3, was shown in
COS cells and in HIT-T15 cells [16, 17]. In the latter cell line,
STAT1 was activated via Y1138 while STAT5B activation occurred via
both Y1138 and Y1077 [17].
Next to JAK-STAT signalling, leptin also activates other
pathways. A number of adaptor molecules can associate with the
receptor and link to several signalling pathways, including the
mitogen-activated protein kinase (MAPK) pathway (see below) and the
phosphoinositol 3-kinase (PI3K) pathway. In the latter, the
JAK2-interacting protein, SH2-B, mediates binding of IRS (insulin
receptor substrate) proteins that function as adaptors for PI3K
[18, 19]. PI3K transforms
phosphatidylinositol4,5-biphosphate (PIP2)
into phosphatidylinositol3,4,5-triphosphate
(PIP3) eventually resulting in reduced levels of cAMP.
It was also demonstrated that leptin has an inhibitory role on
hypothalamic AMPK (AMP-activated protein kinase) activity which
contributes to body weight regulation [20].
Modulation of functional receptor expression
Obviously, receptor internalisation is an effective mechanism for
rapidly turning off cytokine signalling. Upon ligand binding,
cytokine receptors can be internalized via the clathrin-coated pit
pathway into early endosomes. Trafficking dynamics of the LR with
receptor internalisation and subsequent degradation or recycling
back to the cell surface clearly are involved in the regulation of
leptin signalling. In steady-state conditions, no more than 25% of
the LR is located at the cell surface, whilst the majority of the
LR are found in intracellular pools [21]. This distribution of the
LR may be explained by its tendency to constitutive endocytosis
resulting in short-lived membrane expression. In addition, some of
the newly-synthesized LRs are retained intracellularly based on a
retention signal in the transmembrane domain [22]. Whether external
stimuli modulate this LR localisation throughout the cell and in
this way regulate leptin sensitivity remains to be determined.
125I-labeled leptin uptake experiments demonstrated
that LRs are also internalized upon ligand binding via
clathrin-mediated endocytosis leading to leptin degradation in the
lysosomes [21, 23]. An internalisation signal was identified in the
intracellular part of the receptor in immediate proximity to the
membrane [23]. Compared with other LR splice variants, the long LR
isoform seemed to be depleted relatively quickly from the cell
surface upon leptin exposure, suggesting it is most sensitive to
leptin-induced down-regulation while its limited recycling to the
cell membrane was slow [21-24]. This favoured down-modulation of LR
signalling may be implicated in leptin resistance [25, 26].
Recently, it was demonstrated that both the long LR and the
short LR, a membrane-anchored isoform with a short cytoplasmic
tail, become ubiquitinated. Unlike for the long LR, this
ubiquitination is essential for clathrin-mediated endocytosis of
the short LR [27]. Many aspects of the mechanisms underlying LR
cell surface expression and internalisation remain to be
elucidated. It is likely that additional proteins involved in
ubiquitination of the (activated) LR complex remain to be
identified.
A soluble form of the LR associates with circulating leptin
[28]. Secreted cytokine receptors can protect their ligands from
either degradation or clearance and thus significantly extend their
half-life or they can act as antagonists, capturing their ligand
and thus preventing signalling by their membrane-spanning
counterparts. In mice, the soluble LR is generated by alternative
mRNA splicing. In contrast, no such mRNA splice variant has been
discovered in humans; a secreted human LR is generated by
ectodomain shedding of membrane-anchored LRs including the
signalling long form, by a hitherto unknown protease [29-31].
Although the soluble LR appears important for keeping leptin
available in circulation, it is at the same time, capable of
competing with the long LR isoform for leptin binding and may
suppress leptin action in that way [32-35]. This could indicate
that the secreted LR plays an important role in determining leptin
levels available for signal transduction. It is of note that the
relative concentrations of the soluble LR and free leptin are
similar, while in obese individuals concentrations of free leptin
exceed by far the concentrations of secreted LR [36].
Phosphatases
SH2 domain-containing phosphatase-2 (SHP-2) is a constitutively
expressed protein tyrosine phosphatase known to be involved in the
dephosphorylation of the JAKs. It carries two tandem SH2 domains
followed by a tyrosine phosphatase catalytic domain and associates
directly with the LR at position Y985 [37]. The exact role of SHP-2
in LR signalling has been a long standing matter of debate. Despite
its initial identification as an inhibitor of LR signalling (see
below), it also appeared as a strong activator of the MAPK pathway.
ERK activation occurs predominantly via SHP-2 recruitment at
tyrosine Y985 via its C-terminal SH2 domain. SHP-2 is
phosphorylated by JAK2 and forms a docking site for the adaptor
protein growth factor receptor binding 2 (Grb2) leading to the
activation of the ERK signalling cascade [12]. Alternatively, ERK
is also directly activated by JAK2, but still requires the
intervention of SHP-2 [38]. Leptin-triggered activation of MAPK was
observed both peripherally and centrally. Recently, regulation of
calcium fluxes involving MAPK activity was shown in lateral
hypothalamic neurons upon leptin stimulation [39]. Also, NO (nitric
oxide) production induced by leptin via MAPK activation was
observed in white adipocytes [40]. Moreover, leptin induced MAPK is
involved in full activation of the DNA binding of STAT3 by
mediating serine phosphorylation at position S727 of STAT3 [41].
On the other hand, many reports have also attributed an
inhibitory role to the SHP-2 phosphatase in LR signalling. Mutation
of the Y986 position in the human LR led to augmented STAT3
signalling, and inhibitory properties associated with this position
were ascribed to the negative regulatory function of SHP-2 [42].
However, suppressor of cytokine signalling 3 (SOCS3), identified as
a strong inhibitor of LR signalling (see below), was found to
interact with the corresponding Y985 position in the murine LR
[43-45]. SOCS3 is part of the SOCS family and its inhibitory
mechanism is discussed below. SHP-2 and SOCS3 have very similar
binding specificities, and overlapping binding sites were also
observed for the gp130 chain [46-49]. Thus, the negative regulation
associated with the membrane proximal tyrosine position is partly
attributed to SOCS3. However, SHP-2-mediated dephosphorylation of
JAK2 was demonstrated in vitro [37]. Recently, forebrain-specific
SHP-2-deficient mice revealed that SHP-2 moderately down-modulates
JAK2 and STAT3 activation in vivo [50]. Although SHP-2 has a modest
role in terminating leptin signal transduction, its dominant
induction of the ERK pathway makes it overall an enhancer of leptin
signalling, whereby it may function as a switch towards MAPK
signalling.
Protein tyrosine phosphatase 1B (PTP1B) is a crucial protein
tyrosine phosphatase implicated in the negative regulation of
leptin receptor signalling. PTP1B deficiency results in
hypersensitivity to insulin and leptin in mice, and leads to
protection from high fat diet obesity [51]. PTP1B harbours two
phosphotyrosine binding pockets in its catalytic domain that
determine its intrinsic specificity. A consensus substrate
recognition motif was found in the kinase activation loop of the
insulin receptor and in JAK2 [52-54]. Both in vivo and in vitro
data demonstrate that PTP1B targets LR signalling predominantly by
dephosphorylating JAK2 [55-58]. PTP1B is a negative mediator of
both the JAK-STAT and MAPK pathway in leptin receptor signalling.
PTP1B-mediated hypophosphorylation of JAK2 in a mouse hypothalamic
neuronal cell line abrogated the leptin-dependent induction of the
STAT3 and MAPK inducible SOCS3 and c-fos genes, respectively [56].
Recently, leptin induced PTP1B was observed in liver, raising the
possibility that PTP1B may also function in a negative feedback
loop [59]. Diet-induced obesity is associated with increased
hepatic PTP1B levels. Aberrant PTP1B activity is implicated in
leptin resistance and PTP1B is currently being investigated as a
drug target in obesity [60-63].
PTP1B is localized predominantly on the ER (endoplasmic
reticulum) via its C-terminal hydrophobic targeting sequence [64].
How PTP1B acts on its substrates remains unclear. It was
demonstrated that the platelet-derived growth factor (PDGF)
receptor becomes dephosphorylized by PTP1B at the ER after
internalization [65]. Recently, direct interaction of PTP1B with
the insulin receptor was observed in a perinuclear endosome
compartment [66]. On the other hand, it has been demonstrated that
internalisation of the insulin receptor is not essential for
interaction with PTP1B and subsequent dephosphorylation [67]. In
line with this, proteolytic cleavage of PTP1B can lead to the
relocalization of the catalytic domain of PTP1B to the cytosol
[68].
The ubiquitously expressed phosphatase and tensin homologue
deleted on chromosome ten (PTEN) is a tumour suppressor protein and
its mutation is linked with several human cancer types [69]. It
belongs to the family of protein tyrosine phosphatases but also
possesses lipid phosphatase activity. PTEN suppresses the PI3K
pathway by hydrolyzing the secondary messenger PIP3 back
to PIP2. [70]. It was demonstrated that hypothalamic
PI3K is involved in leptin-induced reduction in food intake [19].
Surprisingly, specific disruption of PTEN restricted to the
hypothalamic neurons expressing the anorexigenic
proopiomelanocortin (POMC) neuropeptide results in an obese
phenotype associated with leptin resistance [71].
Suppressors of cytokine signalling
The family of SOCS proteins consists of 8 members: cytokine
inducible SH2 protein (CIS) and SOCS1 through SOCS7. SOCS proteins
have a characteristic domain structure which is represented in (
figure 2 ).
They carry a central SH2 domain, an N-terminal preSH2 domain with
an ESS (extended SH2 subdomain) region and in some cases a kinase
inhibitory region (KIR) domain and a C-terminal SOCS-box [72]. The
N-terminal domain varies in length and composition while the SH2
domain and the SOCS-box are more conserved. They also carry one or
two conserved tyrosines in the C-terminus of their SOCS-box. SOCS
proteins can interfere with cytokine signalling at different
levels. They can interact with phosphotyrosine motifs in activated
cytokine receptor complexes by means of their SH2 domain, thereby
hindering association of signalling molecules. The SOCS-box of SOCS
proteins is identified as a key mediator in targeting associated
proteins for proteasomal degradation. It associates with elonginB/C
via its BC-box and takes part in a multi-protein complex that acts
as an E3 ligase known to link ubiquitin to the substrate. Finally,
the kinase activity of the JAKs can be abolished through the KIR
domain.
SOCS proteins are typically part of a negative feedback loop.
They are induced upon cytokine stimulation and attenuate signalling
by various cytokine receptors, allowing possible cross-regulation
among cytokine systems. Leptin induces SOCS3 expression in a rapid
and transient manner while CIS expression accumulates over a longer
period of time [43, 73, 74]. A role for leptin has also been
implicated in the expression of SOCS1 and, to a lesser extent of
SOCS2 [74, 75].
SOCS3 was identified as a potent inhibitor of LR signalling
[43]. Its STAT3-mediated expression is induced in the hypothalamus
and liver after peripheral leptin administration in
leptin-deficient ob/ob mice [12, 43, 76]. SOCS3 is a functional
marker for identification of leptin-sensitive neurons in the
hypothalamus [77]. In these hypothalamic neurons of the
leptin-resistant lethal yellow (Ay/a) mouse model, elevated levels
of SOCS3 were found [43]. Unlike SOCS3-deficient mice that die in
utero, SOCS3 haploinsufficient or neural-cell specific-deficient
mice are viable and show augmented leptin sensitivity in the
hypothalamus and a remarkable attenuation of diet-induced obesity
[78, 79]. It was demonstrated that SOCS3 action is involved in
rendering the LR refractory to reactivation after chronic leptin
stimulation [80]. These observations show SOCS3 up as a key
mediator of negative regulation of leptin signalling and suggest a
prominent role in leptin resistance.
Only SOCS1 and 3 carry a KIR domain in their N-terminal region
involved in direct inhibition of the JAK kinase activity. They both
inhibit leptin receptor signalling, using a slightly different
mechanism. SOCS1 directly interacts with the kinase domain of JAK2
by targeting the phosphotyrosine at position Y1007 in the
activation loop of JAK2 [81, 82]. The KIR domain is essential for
the inhibitory function of the SOCS protein [82]. It associates
with the catalytic groove of JAK2 and is suggested to act as a
pseudosubstrate which mimics the activation loop that regulates
access to the catalytic groove [81, 82]. It may obstruct the ATP
binding pocket and hinder accessibility for substrates [81, 82].
Unlike SOCS1, SOCS3 has only weak affinity for JAK2. It is thought
to inhibit the kinase activity through its KIR domain after binding
via its SH2 domain with phosphotyrosine motifs in the receptor in
close proximity to the JAKs [83]. Indeed, SOCS3 associates with the
LR at the membrane proximal tyrosine Y985 domain [44, 84]. It also
weakly binds the highly similar Y1077 interaction site, with an
accessory effect on LR signalling inhibition [84].
Using the MAPPIT technique, a two-hybrid method based on
cytokine signalling, we recently demonstrated the interaction of
CIS and SOCS2, two other members of the SOCS protein family, with
the LR [45, 74]. We showed that CIS interacts with the two membrane
proximal tyrosine motifs at positions Y985 and Y1077, while SOCS2
only associated with the latter of the two. Phosphotyrosine
specific interaction of SOCS2 with the LR Y1077 motif was confirmed
by peptide affinity chromatography (PAC). Using this method, we
also demonstrated that SOCS2 binds specifically to the
phosphotyrosine Y1138 peptide. An overview of LR/SOCS interactions
is given in table 1( Table 1 ).
Interactions with the LR Y1138 motif and those involving SOCS1 were
only analysed using PAC since in these cases interference occurs
with the MAPPIT read-out. Of note, MAPPIT proved to be a highly
sensitive technique that can detect weak or transient (but
functionally relevant) interactions that could not be detected by
PAC.
CIS and SOCS2 are known inhibitors of STAT5 activation. Although
negative regulation of a leptin-induced STAT3 binding reporter gene
by CIS was suggested, we did not observe any inhibitory effect on
STAT3-mediated LR signalling by either CIS or SOCS2 [73, 74].
Instead, we suggest an inhibitory role in leptin-induced STAT5
signalling through interference with STAT5a recruitment to the
Y1077 tyrosine motif in a MAPPIT based experiment [74]. Supporting
this notion, SOCS2 binding completely overlaps with STAT5
association at the LR. CIS and SOCS2 may be implicated in
preventing recruitment of downstream signalling moieties to the LR.
Both SOCS2 knock-outs and CIS transgenes show growth abnormalities,
the former being larger and the latter smaller than normal [85,
86]. Although both SOCS proteins are negative regulators of GH
signalling, growth retardation in people with a truncated LR as
well as in LR null db/db mice suggests these SOCS proteins may
additionally influence growth via the LR [15, 87]. Leptin has been
identified as a pro-inflammatory cytokine [88]. It is implicated in
the pathogenesis of several autoimmune diseases including
rheumatoid arthritis, multiple sclerosis and inflammatory bowel
disease [7, 8]. A role for leptin was described in T-cell
proliferation and switching towards a Th1 response [89]. CIS
transgenic mice exhibit a shift to activation of Th2 cells [85], an
effect that may, in part, be explained by its effect on leptin
signalling in T-cells. More detailed analysis in cell-type specific
expression and function will be needed to elucidate the specific
roles of SOCS proteins in leptin signalling. Possibly, different
physiological functions of leptin may be under the control of
different SOCS proteins.
More detailed examination of the binding modalities of SOCS
proteins with the LR reveals that the SOCS-box of CIS is implicated
in the association with the LR (Lavens et al., in press). The
conserved C-terminal tyrosine at position Y253 is essential for
binding to both membrane proximal tyrosines. The same phenomenon is
also observed for interaction with other cytokine receptors such as
the EpoR but not for association with the unrelated MyD88 protein,
an adaptor protein involved in toll-like receptor (TLR) signalling
[74, 90]. In contrast, the corresponding C-terminal tyrosine or
even the entire SOCS-box of the highly related SOCS2 protein are
not essential for interaction with the LR, and deletion of the
SOCS-box also, hardly influenced the inhibitory capacity of SOCS1
or SOCS3 on LR signalling [74]. This indispensable role of the
SOCS-box for binding with the LR (and likely other cytokine
receptors as well), is probably an exclusive characteristic of CIS.
The exact functional role of the C-terminus of CIS is still
unclear. This observation is very reminiscent of the Von
Hippel-Lindau protein whereby the C-terminus of its SOCS-box is
also involved in substrate recognition [91, 92].
Recently, it has become clear that regulation by certain SOCS
proteins can be more complex than a mere negative feedback loop. It
has been demonstrated that, apart from its negative regulatory
effects, SOCS2 can also have positive effects on cytokine
signalling, as was clearly observed in vivo and in vitro for GHR
signalling [93, 94]. SOCS2 interference with other SOCS proteins
has been observed in several cytokine receptor systems including LR
signalling [74, 93, 95, 96, 97]. We recently demonstrated that
SOCS2 interferes with the association of CIS to the membrane
proximal tyrosine of the LR, although no direct binding of SOCS2
with this tyrosine position was demonstrated [74]. In addition,
SOCS2 can impair the inhibitory effect of SOCS1 or SOCS3 on
leptin-induced signalling. This effect strictly relied on the
presence of the SOCS-box of both SOCS-proteins, since deletion of
the SOCS-box of either SOCS2 or SOCS1 and SOCS3 abolished complete
SOCS2 interference [97]. SOCS2 is demonstrated to associate with
all members of the SOCS protein family [74, 96, 97]. Abolishing the
elonginB/C recruitment potential of SOCS2 has no effect on its SOCS
interaction capacity but leads to complete loss of its functional
interfering characteristics [74, 97]. SOCS2 influences the
stability of target SOCS proteins and this effect is sensitive to
proteasome inhibitors and clearly relies on the presence of its
BC-box [96, 97]. Together, these data strongly suggest that SOCS2
can target SOCS proteins for degradation and regulate SOCS protein
turnover. In addition, we demonstrated that SOCS6 and SOCS7 are
also capable of interacting with the SOCS protein family members.
Similar potentiating effects as with SOCS2 are observed for SOCS6
in LR signalling as well as other cytokine receptor systems [97].
This cross-regulatory effect of SOCS proteins may be of great
importance in restoring cellular sensitivity after cytokine
stimulation. Indeed, it has been reported that the expression of
SOCS2 is in many cases more prolonged than that seen for other SOCS
proteins [96-100].
Using the MAPPIT methodology, we recently demonstrated that
SOCS6 and SOCS7 also interact with the LR. Both associate with the
Y1077 motif whilst only SOCS7 interacts with the more membrane
proximal tyrosine [101]. It was reported that SOCS7 is implicated
in LR signalling termination. It can inhibit STAT3 activation which
we speculate may involve LR association, but it can also interact
with activated STAT3 molecules to prevent them from translocating
to the nucleus [102].
Table 1 Binding of the SOCS proteins, CIS and SOCS1
through SOCS3, with the tyrosines of the LR based on peptide
affinity chromatography (PAC) with corresponding phosphorylated and
non-phosphorylated tyrosine motifs and based on mammalian
protein-protein interaction trap (MAPPIT) [74, 84, 100]
|
PY985
|
PY1077
|
PY1138
|
|
MAPPIT
|
PAC
|
MAPPIT
|
PAC
|
PAC
|
|
CIS
|
+
|
-
|
+
|
-
|
-
|
|
SOCS1
|
|
-
|
|
-
|
-
|
|
SOCS2
|
-
|
-
|
+
|
+
|
+
|
|
SOCS3
|
+
|
+
|
- /+
|
+
|
-
|
Conclusion
Leptin is involved in a variety of crucial processes including
adipocyte metabolism and immune responses, and aberrant leptin
signalling has been implicated in several pathophysiological
processes. Tight control mechanisms exist that regulate leptin
receptor signal transduction. Today, SOCS3 and PTP1B are the two
molecules that are most associated with modulation of LR
signalling. However, the involvement of other mechanisms and
molecules, especially other SOCS proteins is emerging. It is likely
that the different inhibitory molecules may be implicated in the
regulation of leptin functions in different cell types. Further
investigation will be needed to clarify the complex regulatory
mechanisms that control leptin receptor signalling in many vital
processes.
Acknowledgements
We greatly acknowledge Prof. Joël Vandekerckhove for continued
support. This work was supported by grants from the Flanders
Institute of Science and Technology (GBOU 010090 grant), from The
Fund for Scientific Research – Flanders (FWO-V Grant N° 1.5.446.98)
and from Ghent University (GOA 12051401).
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