The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, Parkville, Victoria, Australia
Correspondence: Dr. Christopher J. Greenhalgh, The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. E-mail: greenhalgh{at}wehi.edu.au
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Key Words: SOCS Janus kinase STAT PIAS phosphatase
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Much of our understanding of how negative regulation of cytokine signaling is accomplished has focussed on the actions of phosphatases, but more recent research has demonstrated the contributions of newly identified families of inhibitory molecules to this attenuation. This review briefly summarizes what is known about phosphatase regulation of cytokine signaling and then highlights and analyzes two new negative-regulator families, the protein inhibitors of STATs (PIAS) and the suppressor of cytokine signaling (SOCS) proteins.
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[12
]. The
mechanism by which SHP-1 inhibits these pathways is being elucidated
and is thought to involve the deactivation of receptor kinases and
JAKs. SHP-1 has been shown to bind to tyrosine-phosphorylated EPO
receptor and to dephosphorylate JAK2, whereas there are other examples
in which SHP-1 has bound directly to JAK2 via an SH2-independent
mechanism [9
]. SHP-1 is also thought to function by
binding directly to cytokine receptors to dephosphorylate signaling
components. This is emphasized in a Finnish family that has elevated
hematocrit levels because they carry a mutant EPO receptor that is
truncated and unable to bind SHP-1 [13
]. The fact that
SHP-1 is constitutively expressed infers that its inhibitory effects
are rapidly exerted after cytokine receptor activation. This is in
contrast to many SOCS proteins (discussed below), which are expressed
only in response to cytokine signaling.
CD45
Although many membrane-bound phosphatases are known to act in
hematopoietic-signaling pathways, probably the best studied of these is
CD45. CD45 is a transmembrane phosphatase that is highly expressed on
all nucleated hematopoietic cells and has been shown to be extensively
involved in T and B cell antigen receptor signaling and lineage
development, as well as having a role in regulating adhesion and
apoptosis [reviewed in ref 14
]. Only very recently was it discovered
that CD45 also has a function in regulating cytokine signaling. Mast
cells lacking CD45 were found to proliferate faster in response to
interleukin (IL) 3 compared with wild-type cells, implicating CD45 in
regulating IL-3 signaling [15
]. Examination of the
IL-3-signaling cascade identified JAK2 as being hyperphosphorylated in
the absence of CD45 with enhanced JAK2 kinase activity evident within 2
min of IL-3 stimulation. In vitro studies confirmed that CD45 could
directly dephosphorylate JAK2 and identified similar roles for CD45 in
negatively regulating IFN-
and EPO signaling [15
].
Whether CD45 acts on other cytokine-signaling pathways in a similar
manner is unclear at present, but given that it interacts with JAKs,
which are used in many hematopoietic signaling cascades, it is
conceivable that CD45 plays a greater role than currently understood.
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Expression
In contrast to the constitutively expressed phosphatases, SOCS
proteins are induced by a wide range of cytokines such as leukemia
inhibitory factor (LIF), growth hormone (GH), prolactin, many
interleukins, and a host of other growth factors. Table 1
summarizes these data and provides source references,
emphasizes the considerable scope of SOCS functions generated by in
vitro studies, and implicates a number of SOCS proteins as having
pleiotropic actions. The SOCS proteins are found in most hematopoietic
tissues. Northern blot analysis of SOCS mRNA expression patterns has
revealed high levels of CIS in the kidney, fat, muscle, and liver, and
expression of SOCS-1 is found predominantly in the thymus
[16
, 57
]. SOCS-2 mRNA is found in the
liver, heart, lungs, and spleen whereas SOCS-3 is most prevalent in the
lungs, spleen, and fat [16
, 57
]. In vivo
and in vitro cytokine stimulation time-course studies reveal that SOCS
mRNA expression profiles are not identical. For example, SOCS-1 and
SOCS-3 mRNAs have rapid and transient expression profiles that tend to
peak around 1 h but return to baseline by 4 h in response to
GH or IL-6, whereas SOCS-2 initially has lower levels of induction
compared with the other SOCS proteins but increases steadily over a
longer time [16
, 22
]. CIS has a similar
induction profile to SOCS-1, but rather than returning to baseline, its
expression can increase again after 4 h [16
,
22
, 57
]. The reasons for these different
expression patterns are unknown but might reflect differences in their
mechanisms of action.
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View this table: [in a new window] |
Table 1. Induction and Actions of SOCS Proteins
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![]() View larger version (44K): [in a new window] |
Figure 1. Hypothetical mechanism of SOCS-1-negative regulation of JAKs. On
cytokine activation, JAKs are recruited to the receptor complex and
become phosphorylated. Phosphorylation alters the activation loop
conformation from an inactive structure (A) to an active form (B). This
change allows substrates to enter the activation loop region as well as
allowing ATP to bind nearby (C). Kinase activity transfers a phosphate
group (P) from the ATP to the substrate, yielding ADP and
phosphorylated substrate. The subsequent negative-feedback regulation
involves the expression of SOCS-1, which binds to the JAK activation
cleft preventing further activity by restricting recruitment of ATP and
substrate (D). Secondarily to this, components of the proteasome
machinery including elongin B (El B), elongin C (El C), and Cullin 2
(Cul2) bind to the SOCS box and ubiquitinate the signaling complex
and/or the SOCS proteins (E) to target them for
degradation._art>
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Crosstalk mediated by SOCS proteins
Given the large number of cytokines capable of inducing SOCS
protein expression, it is not surprising that a number of hypotheses
have been made implicating SOCS proteins as the mediators of crosstalk
inhibition by opposing cytokine-signaling pathways. For example, it has
been shown that IL-3 can antagonize IL-6-type cytokine (e.g., IL-6 or
IL-11)-driven B-lymphocyte development [65
,
66
]. It has subsequently been shown that the addition of
IL-3 to primary B-cell colonies inhibits IL-11-supported B-cell
development by suppression of IL-11-induced STAT3 phosphorylation,
which involves the synthesis of a protein within 30 min of IL-3
addition [53
]. Analysis of IL-3-induced SOCS mRNA
expression profiles has found that the SOCS-3 temporal expression
pattern correlates well with the negative effects on STAT3
phosphorylation and might be responsible for this inhibition. The
second example of crosstalk involves the state of GH resistance that
develops during sepsis or inflammation, which has been attributed to
the effects of IL-1ß production [67
, 68
].
Recently, Boisclair and colleagues [44
] found that
IL-1ß induces SOCS-3 expression in primary hepatocytes and hepatic
cell lines, but its expression pattern differs from that induced by GH
in that its magnitude is significantly greater, and the expression is
prolonged beyond 24 h after stimulation. This altered expression
pattern has been shown to match the profile of IL-1ß-induced GH
resistance, which requires 824 h to reduce GH-driven transcription of
STAT5-responsive genes [44
]. SOCS-3 has also
been implicated in controlling macrophage responsiveness to IFN-
upon chronic exposure to bacterial lipopolysaccharide.
Lipopolysaccharide induces SOCS-3 mRNA expression in macrophages, and
transfection studies show that SOCS-3 suppresses IFN-
-mediated
transcriptional responses [48
]. Crosstalk using SOCS
proteins might also explain the negative effects of IL-10 on cytokine
signaling. IL-10 is capable of attenuating a range of inflammatory
responses in immune cells [69
], and it is considered to
have negative effects on the actions of IFNs [70
]. IL-10
has been shown to induce SOCS-3 mRNA expression, and it is thought to
be capable of blocking IFN-
-induced STAT1 phosphorylation and
subsequent gene transcription in monocytes [71
].
SOCS knockout and transgenic models
Considerable information has been generated about CIS, SOCS-1, -2
and -3 mechanisms of action and their effects on cytokine signaling,
but this information is clouded by the bewildering number of roles
suggested for them from in vitro experiments. It was anticipated that
genetic deletion studies might reveal insights into the physiological
function(s) of these proteins.
SOCS-1
SOCS-1-/- mice are healthy at birth but die before
weaning due to fatty degeneration of the liver, monocytic infiltration
of organs, reduced thymus size, and significant loss of T- and
B-lymphocytes [72
, 73
]. In addition,
deficits in lymphocyte numbers and selective depletion of maturing
B-lymphoid cells have also been observed. SOCS-1-/-
spleen weights are not significantly different from those of normal
mice, but they are devoid of lymphoid follicles or composed of immature
cells. It is interesting that the SOCS-1-/- phenotype is
reminiscent of that induced by elevating IFN-
levels in neonatal
mice [74
, 75
]. Subsequent work has shown
that the SOCS-1-deficient phenotype can be corrected with
administration of antibodies against IFN-
or by crossing mice with
IFN-
-/- mice [33
, 76
],
identifying IFN-
as an essential component in the manifestation of
the phenotype. The hypothesis that SOCS-1 controls IFN-
sensitivity
is strengthened by the fact that SOCS-1-/- macrophages
have enhanced IFN-
-mediated killing of Leishmania
parasites and a hyperresponsive reaction to viral infection
[33
]. These results support a model of
hyperresponsiveness to IFN-
, but the phenotype is compounded by the
fact that SOCS-1-/- mice also have elevated IFN-
levels, raising the question of the source of the excessive cytokine
production. Reconstitution of irradiated JAK3-deficient mice with
SOCS-1-/- bone marrow can confer the lethal
SOCS-1-/- phenotype, implying that lymphocytes might
mediate at least some of the phenotype. Strong support for this
hypothesis is also obtained by crossing SOCS-1-/- mice
with mice deficient in RAG2, resulting in a rescue of the phenotype in
a manner similar to that when SOCS-1-/- mice are crossed
with IFN-
-/- mice [76
]. Taken together,
these results indicate that SOCS-1 attenuates IFN-
signaling as well
as playing a role in controlling the production of this cytokine.
Given the in vitro data suggesting a pleiotropic role for SOCS-1 in
many signaling systems, it was somewhat surprising to find a limited,
yet extremely potent role for SOCS-1 in regulating IFN-
signaling.
However, there are now indications that other more subtle
phenotypes could be present in the SOCS-1-/- mice.
SOCS-1-/- embryonic fibroblasts have been shown to be
more sensitive to tumor necrosis factor (TNF)-
, but the relevance of
these findings is unclear at present [36
]. In addition,
these embryonic fibroblasts display enhanced insulin-induced
differentiation into adipocytes, and mice devoid of SOCS-1 have
significantly elevated levels of glucose [77
]. These
results suggest that SOCS-1 plays a role in regulating insulin signal
transduction. The mechanism of this action is uncertain, but
overexpression of SOCS-1 inhibits insulin-induced insulin receptor
substrate-1 phosphorylation via blockade of JAK1 action
[77
]. Other lines of evidence also suggest that SOCS-1
might play additional physiological roles that are yet to be
identified. Mice with transgenic overexpression of SOCS-1 in T cells
have impaired IL-6 and IL-7 signaling in addition to inhibited IFN-
action. These mice also have reduced thymocyte populations,
significantly increased CD4/CD8 ratios, and expression of activation
markers in splenic T cells [78
]. Together, these results
imply that SOCS-1 plays a role in T-cell development and homeostasis.
The relevance and importance of these findings are yet to be
established, but the roles of SOCS-1 are beginning to be unraveled.
SOCS-2
Although the previously described SOCS members have clear
physiological roles in the immune system, the recently generated
SOCS-2-/- mice have no detectable defect in their
hematopoietic systems. It was not until 6 weeks of age that male
SOCS-2-deficient mice were found to be significantly larger than
wild-type mice, manifesting a 40% increase in size by 12 weeks
of age [79
]. Most organs also become significantly
larger but in proportion to the overall increase in size of these
animals. Furthermore, the long bones and nose-to-tail lengths increase
significantly in SOCS-2-deficient animals. Similar growth abnormalities
have also been observed in female SOCS-2-deficient animals, although
these are not quite as severe. Histological examinations of
SOCS-2-/- animals have found a marked thickening of the
dermis characterized by excessive collagen accumulation, as well as
some collagen deposition in organ ducts and vessels.
SOCS-2-/- mice have significantly lower levels of MUP
(major urinary protein), a GH-pulsatile product that is down-regulated
in mice lacking or overexpressing GH [80
]. Insulin-like
growth factor (IGF)-I production is also controlled to a certain extent
by GH, but analysis of circulating IGF-I levels has failed to detect
any significant difference in IGF-1 production between wild-type and
SOCS-2-deficient animals. However, emerging models of GH/IGF-I
induction indicate that local autocrine/paracrine production of IGF-I
is more important for growth than circulating, liver-derived IGF-I
[81
, 82
]. RNase protection assays have been
performed on a number of organs and have found significantly elevated
levels of IGF-I mRNA in the heart, lung, and spleen but not in the
bone, liver, fat, or muscle. These results indicate that SOCS-2 plays
an important role in controlling some component(s) of postnatal growth,
and there is evidence that the GH/IGF-I axis is a focus of its action.
SOCS-3
Ablation of SOCS-3 again demonstrates the important role SOCS
proteins play in regulating cytokine signaling. SOCS-3-/-
mice die between embryonic days 12 and 14 due to massive erythrocytosis
surrounding the fetal liver and abdominal region, whereas
overexpression of SOCS-3 completely blocks all fetal liver
hematopoiesis [83
]. Analysis of SOCS-3-/-
progenitor cells has found that they are hyperresponsive to IL-3 and
EPO, and although reconstitution of lethally irradiated wild-type mice
with SOCS-3-/- fetal liver cells fails to identify any
role for SOCS-3 in normal adult hematopoiesis, hematopoietic
progenitors from these mice exhibit enhanced responsiveness to a number
of cytokines [83
]. Together, this work suggests that
SOCS-3 plays a crucial role in limiting erythroid-lineage expansion.
Unfortunately, any potential role(s) of SOCS-3 in other signaling systems has not been evaluated because of the developmental block generated by the lethal phenotype, but it is hoped that future gene-targeting strategies using Cre/lox recombination and conditional gene targeting will bypass this impediment.
CIS
In contrast to the striking phenotypes of SOCS-1-, -2-, or
-3-deficient mice, deletion of CIS fails to reveal any phenotypic
changes in mice [83
], and transgenic models are required
for gaining any indications as to the physiological function of CIS.
Enforced expression of CIS induces a phenotype similar to that observed
with the STAT5a-/- and STAT5b-/- mice
[84
85
86
], encompassing incomplete mammary gland
involution and reduced whey acidic protein expression,
dwarfing/feminization of males, reduced levels of GH-induced MUP,
suppression of STAT5 phosphorylation, and a reduced T cell response to
IL-2 stimulation [87
]. These mice also have
significantly lower numbers of 
T cells and natural killer, and
natural killer-T cells. In addition, CIS-transgenic mice
generated a significantly higher proportion of Th2 type T cells after T
cell receptor stimulation, compared with wild-type mice. These findings
strongly suggest that the physiological functions of CIS are to
negatively regulate STAT5 contributions to growth, mammary gland
function, and T cell development.
PIAS
The PIAS family of molecules was discovered in yeast two-hybrid
screens designed to identify STAT-interacting proteins. Database
searches with an interacting candidate molecule termed PIAS1,
identified it to be part of a family of structurally related proteins
that share a putative zinc-binding domain, a highly acidic region, and
>50% homology at the amino acid level to other family members
[88
]. Unlike SOCS proteins, which are expressed upon
cytokine stimulation, PIAS1 is constitutively expressed in a number of
cell lines. However, overexpression studies discovered that PIAS1 binds
only to activated STAT1 dimers and inhibits their DNA-binding activity,
whereas monomeric forms of STAT1 are not bound [88
].
Deletion studies with PIAS1 mutants defined a region in the C terminus
of the protein that interacts with an N-terminal domain of the STAT1
dimer (called the STAT-interacting domain) [89
], but no
role has been ascribed to the putative zinc-binding domain.
Recent work investigating the regulation of STAT1 activity has further defined the nature of the STAT1/PIAS1 interaction. Mowen and colleagues [90 ] discovered that STAT1 dimers are methylated on a conserved arginine residue, a modification that greatly increases their ability to bind DNA and initiate gene transcription. With the use of methylation inhibitors, it was found that methylation prevents PIAS1 from binding to activated STAT dimers, whereas inhibition of methylation allows PIAS1 to freely interact with these dimers and inhibit their DNA binding and transcription actions. Cells which have been genetically altered to be incapable of breaking down methylation inhibitors that are normally generated in cells, and thus have high levels of methylation inhibitors, have been shown to have greatly reduced STAT1 DNA-binding activity because PIAS is capable of binding to a higher proportion of STAT1 dimers [90 ]. These observations might have important clinical applications given that some cancers lack the ability to regulate methylation inhibitor levels [91 ].
PIAS3 is constitutively expressed in a wide range of tissues and subsequently interacts specifically with phosphorylated STAT3 molecules in IL-6-stimulated M1 cells [92 ]. This phenomenon is also induced by other IL-6 type cytokines, and like PIAS1, PIAS3 activity ablates all STAT3-mediated gene transcription. Thus, two members of the PIAS family target specific STAT molecules to dampen their activities. The constitutive expression of these molecules implies that their physiological function differs from that of SOCS proteins, which are induced in a classical negative feedback loop on cytokine stimulation. Consequently, PIAS proteins may act like a buffer that titrates the concentration of active STAT dimers within the cell. However, most of the data compiled on PIAS function rely heavily on in vitro yeast two-hybrid and overexpression studies. Gene deletion studies in mice could be extremely informative in deciphering PIAS physiological functions, as they have been for the SOCS proteins.
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![]() View larger version (100K): [in a new window] |
Figure 2. Mechanism of negative regulation of the JAK/STAT pathway. Cytokine
binds to its receptor causing receptor dimerization and
phosphorylation, leading to the recruitment of JAKs that
cross-phosphorylate before phosphorylating the receptor. STAT molecules
bind to phosphorylated docking sites, are in turn phosphorylated,
dimerize, and enter the nucleus where they initiate transcription. Some
of these genes activated are SOCS family members, which in turn bind
and deactivate JAKs and occupy receptor STAT-binding sites. SHP-1 binds
to the activated receptor before dephosphorylating the JAKs, and PIAS
molecules bind to active STAT dimers preventing them from binding to
DNA. Not shown are mechanisms for receptor complex internalization and
degradation._art>
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Received April 24, 2001; revised May 31, 2001; accepted June 6, 2001.
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K. S. A. Khabar, Y. M. Siddiqui, F. Al-Zoghaibi, L. Al-Haj, M. Dhalla, A. Zhou, B. Dong, M. Whitmore, J. Paranjape, M. N. Al-Ahdal, et al. RNase L Mediates Transient Control of the Interferon Response through Modulation of the Double-stranded RNA-dependent Protein Kinase PKR J. Biol. Chem., May 23, 2003; 278(22): 20124 - 20132. [Abstract] [Full Text] [PDF] |
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O. Galm, H. Yoshikawa, M. Esteller, R. Osieka, and J. G. Herman SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma Blood, April 1, 2003; 101(7): 2784 - 2788. [Abstract] [Full Text] [PDF] |
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O. A. Malakhova, M. Yan, M. P. Malakhov, Y. Yuan, K. J. Ritchie, K. I. Kim, L. F. Peterson, K. Shuai, and D.-E. Zhang Protein ISGylation modulates the JAK-STAT signaling pathway Genes & Dev., February 15, 2003; 17(4): 455 - 460. [Abstract] [Full Text] [PDF] |
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D. C.H Ng, N. W Court, C. G dos Remedios, and M. A Bogoyevitch Activation of signal transducer and activator of transcription (STAT) pathways in failing human hearts Cardiovasc Res, February 1, 2003; 57(2): 333 - 346. [Abstract] [Full Text] [PDF] |
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T. Kuwata, C. Gongora, Y. Kanno, K. Sakaguchi, T. Tamura, T. Kanno, V. Basrur, R. Martinez, E. Appella, T. Golub, et al. Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element Mol. Cell. Biol., November 1, 2002; 22(21): 7439 - 7448. [Abstract] [Full Text] [PDF] |
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C. J. Greenhalgh, D. Metcalf, A. L. Thaus, J. E. Corbin, R. Uren, P. O. Morgan, L. J. Fabri, J.-G. Zhang, H. M. Martin, T. A. Willson, et al. Biological Evidence That SOCS-2 Can Act Either as an Enhancer or Suppressor of Growth Hormone Signaling J. Biol. Chem., October 18, 2002; 277(43): 40181 - 40184. [Abstract] [Full Text] [PDF] |
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O. Zolk, L. L. Ng, R. J. O'Brien, M. Weyand, and T. Eschenhagen Augmented Expression of Cardiotrophin-1 in Failing Human Hearts Is Accompanied by Diminished Glycoprotein 130 Receptor Protein Abundance Circulation, September 17, 2002; 106(12): 1442 - 1446. [Abstract] [Full Text] [PDF] |
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Y. E. Timsit and D. S. Riddick Stimulation of Hepatic Signal Transducer and Activator of Transcription 5b by GH Is Not Altered by 3-Methylcholanthrene Endocrinology, September 1, 2002; 143(9): 3284 - 3294. [Abstract] [Full Text] [PDF] |
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C. Berlato, M. A. Cassatella, I. Kinjyo, L. Gatto, A. Yoshimura, and F. Bazzoni Involvement of Suppressor of Cytokine Signaling-3 as a Mediator of the Inhibitory Effects of IL-10 on Lipopolysaccharide-Induced Macrophage Activation J. Immunol., June 15, 2002; 168(12): 6404 - 6411. [Abstract] [Full Text] [PDF] |
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R. Buettner, L. B. Mora, and R. Jove Activated STAT Signaling in Human Tumors Provides Novel Molecular Targets for Therapeutic Intervention Clin. Cancer Res., April 1, 2002; 8(4): 945 - 954. [Abstract] [Full Text] [PDF] |
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