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Birkhuser Verlag, Basel, 2001

Inflamm. res. 50 (2001) 435 441


1023-3830/01/090435-07 $ 1.50+0.20/0 Inflammation Research

Review

Biological and clinical significance of the JAK-STAT pathway;


lessons from knockout mice
P. Igaz 1, S. Tth 2 and A. Falus 2
1 2nd Department of Medicine, Semmelweis University, Faculty of Medicine, H-1088 Budapest, Szentkirlyi utca 46, Hungary
2
Department of Genetics, Cell- and Immunobiology, Semmelweis University, Medical School, H-1089 Budapest, Nagyvrad tr 4, Hungary,
Fax: ++36 1 303 69 68, e-mail: FALAND@dgci.sote.hu

Received 30 November 2000; returned for revision 15 January 2001; returned for final revision 29 March 2001; accepted by E. Neugebauer 8 May 2001

Abstract. Originally described as the signal-transducing For the initiation of the JAK-STAT pathway, dimerisation
pathway of interferons, the JAK-STAT pathway soon turned of the signal-transducing subunits seems to be indispensable.
out to participate in the signalling of numerous other immune This is generally triggered by the association of the ligand-
and even non-immune mediators. Several murine knockout bound receptor subunit with the signal-transducing chain. As
models have been described that underline the biological sig- a result of this, the JAK-kinases that are constitutively asso-
nificance of this signalling system. Some human diseases ciated with the cytoplasmic portions of these subunits are
(mainly neoplastic) are also known where malfunctioning of activated [4]. JAK(Janus)- kinases contain both a kinase and
the JAK-STAT pathway is considered to participate in the a pseudokinase domain without catalytic activity. Once acti-
pathogenesis. In this brief review article we will try to make vated, JAKs phosphorylate the neighbouring JAKs, receptor
a synopsis of its biological and clinical significance. subunits and several other substrates on tyrosines. Four
mammalian JAK proteins have been described to date (JAK1,
Key words: Cytokine JAK-STAT SOCS Knockout JAK2, JAK3, TYK2). Among the JAK substrates, STAT pro-
teins (signal transducers and activators of transcription) are
the most important [3, 5, 6].
STAT proteins are latent transcription factors that are
Introduction and synopsis of the JAK-STAT machinery located in the cytoplasm in the resting state of the cell, and
upon phosphorylation on a single tyrosine performed by JAK
Although first described as the signal-transducing pathway kinases they dimerise via their SH2 (src-homology 2)
of interferons, the JAK-STAT system soon turned out to be domains, and migrate into the nucleus where they activate
utilized by numerous cytokines and even primarily non- different genes [5, 7]. Seven mammalian STAT proteins have
immune mediators (e.g. growth factors, hormones) [1]. Sev- been so far recognized. Among these STAT5A and STAT5B
eral different types of receptors were shown to activate the are encoded by highly homologous adjacent genes [5]. Both
JAK-STAT pathway. These include receptors with intrinsic homo- and heterodimers of different STATs have been
protein tyrosine kinase (PTK) activity (RTK: receptor tyro- described. For the full activity of STAT proteins serine phos-
sine kinases), receptors without PTK activity (non-PTK-R), phorylation is also required [8], that can possibly be per-
and G-protein-coupled receptors [2] (Table 1). Among these, formed e.g. via the MAPK (mitogen activated protein kinase)
cytokine receptors without PTK activity, appear to be the pathway [7]. Different patterns of JAK and STAT molecules
most important. These receptors generally consist of multiple seem to be activated by different cytokine receptors, this is
chains with different functions (ligand-binding, and signal- supposed to play fundamental roles in conferring specificity
transducing chains). Based on the common presence of for cytokine responses [2, 3] (Table 1).
receptor subunits responsible for signal-transduction, the Recent data suggest that several inhibitory mechanisms
cytokine receptor family can be further subdivided in small- are involved in the regulation of the JAK-STAT pathway to
er groups, e.g. interleukin (IL)-6 type, IL-2 type, IL-3 type prevent it from over-activation. A new family of cytokine-
[3]. induced inhibitory proteins has been discovered in recent
years. The first member of this family was termed CIS
(cytokine inducible SH2-containing protein) that was found
Correspondence to: A. Falus to inhibit IL-3 and EPO signalling [9]. Later investigations
436 P. Igaz et al. Inflamm. res.

Table 1. Cytokines (and other mediators) activate different patterns of JAK and STAT molecules. Summary of the most important observations.

Receptor group MEDIATORS JAKs STATs

Non-PTK-R (gp130) heteromeric IL-6 type cytokines JAK1, JAK2, TYK2 STAT3, STAT1, STAT5
Non-PTK-R (gp140) heteromeric IL-3 type cytokines JAK2 STAT5
Non-PTK-R (gc) heteromeric IL-2 type cytokines JAK3, JAK1 STAT5, STAT3, STAT1
IL-4, IL-13: STAT6
Non-PTK-R heteromeric interferons JAK1, JAK2, TYK2 STAT1, STAT2, STAT3, STAT5;
and IL-10 STAT1, STAT3
Non-PTK-R single chain receptors GH, PRL, EPO, TPO JAK2 STAT5
RTKs EGF, PDGF, CSF-1 JAK1, JAK2, TYK2 STAT1, STAT3, STAT5

G-protein-coupled 1. chemokines e.g. SDF1-a, JAK1, JAK2, JAK3 STAT1, STAT3, STAT5
receptors RANTES, MCP-1, MIP-1a]
2. angiotensin-II via AT1 JAK2, TYK2 STAT1, STAT2
receptor

Heteromeric receptors contain different subunits with mainly distinct functions (e.g. ligand-binding and signal-transducing), whereas single chain
receptors are constituted by a single type of receptor subunit. The common signal transducing chain (where available) in heteromeric Non-PTK-R-s
is indicated in brackets. (CSF-1: colony-stimulating factor 1, EGF: epidermal growth factor, EPO: erythropoietin, GH: growth hormone, MCP-1:
monocyte chemotactic protein, MIP1-a: macrophage inflammatory protein 1-a, Non-PTK R: receptor without protein tyrosine kinase activity,
PDGF: platelet-derived growth factor, PRL: prolactin, RANTES: regulated upon activation, normal T-cell expressed and secreted, RTK: receptor tyro-
sine kinases, SDF: stromal cell-derived factor, TPO: thrombopoietin).

revealed additional members of this family. These proteins Members of another inhibitory protein family, PIAS (pro-
have several alternative names: SOCS (suppressor of tein inhibitors of activated STAT) proteins are not induced by
cytokine signalling) [10], SSI (STAT-induced STAT STAT proteins [21]. They are supposed to function in a buffer
inhibitor) [11]) and JAB (JAK binding protein) [12]), but like manner, as they seem to be constitutively expressed, and
they are also sometimes called CIS, distinguished from the by inhibiting the actions of STATs (by unknown mecha-
original by consecutive numbering. In the following the term nisms) may represent a permanent inhibitory mechanism
SOCS will be used. The SOCS family of proteins currently [19, 22]. Figure 1 shows a schematic illustration of the
contains eight members (CIS and SOCS1-7) [13]. (SOCS1 is JAK-STAT pathway.
equivalent to SSI-1 and JAB.) The promoter of CIS and pos- STAT proteins were reported to interact with several
sibly SOCS1 protein genes contain STAT responsive ele- other signalling molecules including transcription factors
ments [12, 14]. The transcription of SOCS genes is supposed (e.g. glucocorticoid receptor, c-jun, SMAD proteins [media-
to be stimulated by STAT dimers and the synthesised SOCS tors of transforming growth factor b signalling], adenovirus
proteins in turn inhibit the JAK-STAT pathway, thus consi- E1A protein etc.), thus STATs not only directly influence the
tuting a negative feedback loop. Three different mechanisms
were proposed in the functioning of SOCS proteins: i.SOCS-1
seems to interact directly with JAK kinases and to inhibit
their catalytic activity [15]; ii. SOCS-3 appears to bind to the
receptor signal-transducing chain (gp130 in the case of IL-6
type cytokines), and possibly inhibits JAK activation [16]; iii.
CIS binds to the activated cytokine receptor and competes
with STATs for the access to docking sites [9, 17]. Consider-
ing the mechanism of CIS action that differs from that of
SOCS1 and SOCS3, it appears to be wise to reserve the term
CIS for the first discovered member of this protein family. It
has been proposed that after these initial interactions, signal
termination turns complete when the SOCS/JAK complex is
targeted for proteosomal degradation [18].
SHP-1 and SHP-2 phosphatases also participate in the
negative regulation, by dephosphorylating the JAK and
STAT proteins [19]. The SHP-2 phosphatase also takes part
in the activation of the MAPK pathway that besides being a
main regulator of cell-proliferation, can also modulate STAT
activity via serine-phosphorylation. The C-terminal part of
SHP-2 contains docking elements for the adaptor protein
Grb2 that is constitutively associated with the GTP exchange
factor Sos. The SHP2-Grb2-Sos route thereby leads to the Fig. 1. Schematic illustration of the JAK-STAT pathway. Y: tyrosine.
activation of the Ras kinase, and thus results in the induction (Abbreviations are explained in the text.; indicates negative, + positive
of the MAPK pathway [20]. regulation).
Vol. 50, 2001 Significance of the JAK-STAT pathway 437

expression of their target genes, but may modulate the func- infections that coincides with the prominent functions of
tioning of several other signal-transducing pathways too [7]. these STATs in interferon signalling [3235]. STAT3 knock-
In the following, we attempt to briefly summarise the outs die before birth, the embryos show severe developmen-
findings demonstrating the biological and clinical signifi- tal abnormalities [36]. This suggests that the importance of
cance of this pathway. STAT3 extends beyond the immune system.
STATs were found to participate both in the induction of
(STAT1 and STAT3) and in the protection from (STAT3 and
Biological significance of the JAK-STAT pathway STAT5) apoptosis. STAT3 seems to be able to regulate apop-
tosis in both positive and negative directions [37]. The impor-
The in vivo importance of the JAK-STAT pathway is under- tance of STATs in proliferation and differentiation is well
lined by murine knockout models. Knockout models for documented. Similar to the regulation of apoptosis STATs
almost all known JAK and STAT proteins have been were found to exhibit both stimulatory and inhibitory actions
described to date. on proliferation and differentiation. Among STATs, STAT1,
These knockout models provide invaluable information STAT3 and STAT5 were found to be the most important in
concerning the functions of these molecules, since the inter- these processes. These STATs were found to interact with
actions of these proteins are so complex that in vitro models several different signal-transducing pathways, and thus to
could hardly present a clear picture. participate in sophisticated regulatory networks [37]. STAT4
Whereas knockout animals for JAK1 and JAK2 are not and STAT6 appear to influence the differentiation of T-cells
viable, JAK3 and TYK2 knockouts survive and are even fer- [35]. The JAK-STAT pathway also appears to be implicated
tile [6]. JAK1-deficient mice die perinatally and exhibit pro- in the development of the mammalian forebrain [38].
found defects in lymphoid development. Defects in respons- The generation of STAT4 and STAT6 knockouts served in
es to the cytokines IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-13, vivo evidence of the T-helper cell polarization (Th1-Th2).
IL-15, leukemia inhibitory factor (LIF) and interferons were STAT4 knockout mice show Th responses shifted in the Th2
observed [23]. JAK2 knockout mice die in the embryonic direction, since STAT4 is the main transcription factor of IL-
period. No erythropoiesis was observed in the JAK2 defi- 12 that primarily promotes cytotoxic responses. In STAT4
cient mice that correlates with the significant role of JAK2 in deficient mice decreased NK-cell cytotoxicity and abrogated
erythropoietin (EPO), thrombopoietin (TPO), IL-3 and IL-5 interferon-g production upon IL-12 challenge were observed
signalling [24, 25].The survival of JAK3 animals can be [39, 40]. STAT6 knockout mice, on the other hand, seem to
associated with the limited expression of this JAK kinase [6], have diminished Th2 (e.g. allergen induced airway inflam-
since it is mainly expressed in cells of the lympho- mation and resulting eosinophilia) and enhanced Th1
haematopoietic lineages. As JAK1 and JAK2 appear to show responses that coincides with the prominent role of STAT6 in
widespread distribution and important signal-transducing IL-4 signalling [41, 42]. Therefore, these knockout models
functions in several cytokine actions, the lack of viability of present in vivo evidence of the phenomenon of T-cell
the corresponding knockouts is not surprising. JAK3 knock- dichotomy, that can be deduced even to the level of tran-
out mice suffer from the murine SCID (severe combined scription factors.
immune deficiency) that severely affects both B- and T-cell STAT5A knockouts do not show severe abnormalities,
populations [2628]. The phenotype of mice lacking the except defects in mammary gland development [43]. Actual-
common g-chain, that is involved in the assembly of recep- ly STAT5 was originally described as a prolactin induced
tors for IL-2, IL-4, IL-7, IL-9 and IL-15, is virtually indistin- transcription factor [44]. Analysis of STAT5b knockout mice
guishable from that of JAK3 knockouts [29, 30]. The com- indicated an indispensable role for STAT5b in sexually
mon g-chain was found to be associated with JAK3 [31], dimorphic growth hormone actions [45]. The proliferation
demonstrating that the lack of the common g-chain and JAK3 and differentiation of T- and NK-cells was impaired in both
affect the same signalling pathway (Table 2). STAT5a and STAT5b deficient mice [46, 47]. STAT5a/
Among the STAT knockouts, all knockout models except STAT5b double knockout mice have also been generated
STAT3 are viable, but significant differences can be [48]. These double knockout mice have no NK-cells, under-
observed regarding their defects. STAT1 and STAT2 knock- lying the importance of STAT5 molecules in NK-cell devel-
outs suffer from increased susceptibility to mainly viral opment, and the T-cells from these animals fail to proliferate
in response to anti-CD3 stimulation [49] (Table 3).
Knockout mice lacking the SOCS-1 protein are not
Table 2. The phenotypes of JAK knockout mice.
viable. They die 23 weeks after birth, show severe lym-
JAK kinase Cytokines whose actions Phenotype Ref. phopenia, fatty degeneration of the liver and macrophage
are affected infiltration of several organs [5052]. Naka et al. found that
the severe lymphopenia might be associated with the
JAK1 interferons die perinatally, [23] enhanced apoptosis of lymphocytes that appeared to be relat-
small ed to the augmented expression of the pro-apoptotic protein
IL-2 type (gc-dependent) small at birth,
cytokines no nursing Bax [53]. Recent investigations found an excessive produc-
tion and response to IFN-g in SOCS-1 deficient mice [52,
JAK2 EPO, TPO, IL-3, embryonic lethality, [24, 25]
GM-CSF, IFN-g no erythropoiesis 54]. In fact, the administration of high doses of IFN-g to
neonatal mice produces a syndrome that is strikingly similar
JAK3 IL-2 type (gc-dependent) SCID [26, 27]
cytokines SCID to that of SOCS-1 deficient mice [55]. Treatment of SOCS-1
deficient mice with anti-IFN-g antibodies prevented disease
438 P. Igaz et al. Inflamm. res.

Table 3. The phenotypes of STAT knockout mice. Table 4. The phenotypes of SOCS-deficient mice.

STAT protein Phenotype Ref. SOCS-protein Phenotype Ref.

STAT1 and defects in IFN-signalling, susceptibility [3235] SOCS-1/ perinatal death (within 3 weeks), [50 53]
STAT2 to (viral) infections + IFN- g+/+ increased IFN-g production,
STAT3 early fetal death [36] liver degeneration, lymphoid
deficiencies
STAT4 unresponsiveness to IL-12 [39, 40]
Th1 development impaired SOCS-1/ phenotypically normal [54]
+ IFN- g/
STAT5a defect in lactation, impaired PRL [43]
signalling SOCS-1/ fatal myocarditis and polymyositis [56]
+ IFN- g+/ (death within 160 days)
STAT5b loss of sexually dimorphic growth, [45]
defective GH signalling SOCS-2 gigantism, impaired IGF-1 production [58]
STAT5a/ no NK-cells [48, 49] SOCS-3 embryonic lethality, marked [59]
STAT5b defective IL-2-induced T cell proliferation erythrocytosis
female infertility
(/: homozygous deletion of the allele, /+: heterozygous, one copy of
STAT6 defect in Th2 development [41, 42] the allele, +/+: homozygous alleles present, IGF-1: insulin-like growth
impaired IL-4/IL-13 signalling factor 1).

Fusion proteins of JAK2 and Tel (an Ets family transcrip-


development, and double knockout mice lacking both tion factor) were found in some acute lymphocytic
SOCS-1 and IFN-g also remained alive [54]. In addition, leukaemias [63]. In HTLV-1 (human T-cell lymphotropic
SOCS-1 knockout mice that are heterozygous for IFN-g live virus 1) infected T-cells, the sustained activation of JAK-
longer than mice having both copies of the IFN-g gene, but STAT pathway is supposed to result in malignant transfor-
eventually die from fatal myocarditis and polymyositis [56]. mation [64].
The fatty degeneration of liver cells is supposed to be associ- Among STATs, STAT3 seems to participate most fre-
ated with the incapability of SOCS-1 negative hepatocytes to quently in malignant development. STAT3 overactivation
appropriately regulate cytokine responses [57]. SOCS-2 was described in multiple myeloma, mycosis fungoides (a T-
deficient mice appeared to develop gigantism that may be cell cutaneous lymphoma), in chronic myelogenous leukemia
related to the deregulated signalling of growth hormone and (CML) [6567]. Actually, STAT3 was found to be constitu-
insulin-like growth factor 1 (IGF-1) in these animals [58]. tively phosphorylated on tyrosine in mycosis fungoides cells,
SOCS-3 seems to be involved in the regulation of fetal liver and inhibition of STAT3 DNA binding resulted in apoptosis
erythropoiesis. Embryos of transgenic mice overexpressing induction [66]. Activation of the JAK-STAT pathway was
SOCS3 were found to lack fetal liver erythropoiesis, where- also found in other T-cell lymphomas as well [64, 68]. Con-
as SOCS-3 deficient mice also experience embyonic lethali- stitutive activation of the JAK-STAT pathway was described
ty. SOCS-3 deficient embryos were shown to have a marked in acute myelogeneous leukemia and in megakaryocytic
erythrocytosis in relation to an extremely active erythro- leukemic cell lines as well [69, 70]. In leukemic cells (main-
poiesis that destroyed the liver and many other organs as well ly CML blasts, but also in some cases of acute myelogeneous
[59] (Table 4). and lymphocytic leukemias) the bcr-abl fusion oncoprotein
SHP-1 deficient mice are called motheaten. They suffer was found to phosphorylate and activate the JAK-STAT path-
from a syndrome involving autoimmunity and over-prolifer- way [67, 71]. In chronic lymphocytic leukemia patients con-
ation of hematopoietic cells [60]. The lack of SHP-2 expres- stitutive serine phosphorylation of STAT3 and STAT1 was
sion results in embryonic lethality at midgestation, this, how- observed [72]. Since serine phosphorylation of STATs is
ever, seems to be primarily associated with defective epider- required for full activity [8], this finding may have patho-
mal growth factor signalling [61]. Since SHP-1 and SHP-2 genetic relevance. Besides lymphohaemopoietic tumours,
are involved as regulators of numerous signal-transducing increased STAT expression was also described in cancers of
pathways apart from the JAK-STAT system (e.g. natural the head-neck region and meningiomas [73, 74].
killer cell receptors, B- and T-cell receptors, c-kit receptor, In addition to neoplastic diseases, similar to the above
FcgRIIB etc. [62]), the defects in these knockouts are the described case of JAK3 knockout mice, the human SCID
cumulative results of the malfunctioning of several different phenotype is in part also associated with defects of the JAK-
signalling pathways. STAT system. Two forms of human SCID related to JAK-
STAT system malfunctioning are known, that differ in their
inheritance patterns [75]. Autosomal recessive SCID is asso-
Clinical observations ciated with JAK3 mutations, while X-recessive is the result
of mutations of the common g-chain [7678]. Although the
The majority of clinical data, where JAK-STAT system mal- pathogenesis seems to be similar in both human and murine
functioning is presumed to be associated with disease devel- diseases several differences can be observed. In mice, both
opment involves mainly lymphohaemopoietic neoplastic dis- B- and T-cell lineages are severely affected, whereas in
eases, but the pathogenesis of other diseases e.g. myocardial humans the number of B-cells was found to be normal, nev-
hypertrophy and bronchial asthma also appear to involve dis- ertheless these B-cells are non-functional. In humans mature
turbances of the JAK-STAT pathway. T-cells are not detected, in older mice, however, normal num-
Vol. 50, 2001 Significance of the JAK-STAT pathway 439

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