Vous êtes sur la page 1sur 7

Birkhuser Verlag, Basel, 2001

Inflamm. res. 50 (2001) 435 441

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


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
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

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

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
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

bers of peripheral CD4+ T-cells were found, but these are non- References
functional [28, 75]. The difference in B-cell numbers be-
tween humans and mice SCID patients may be related to [1] Kishimoto T, Taga T, Akira S. Cytokine signal transduction. Cell
the finding that IL-7 that signals via gc and JAK3 is a pre-B- 1994; 76: 25362.
cell growth factor in mice, but not in humans [79]. These [2] Heim MH. The JAK-STAT pathway: specific signal transduction
observations indicate that considerable species differences from the cell membrane to the nucleus. Eur J Clin Invest 1996;
may exist between human and murine diseases, therefore 26: 112.
findings of an experimental disease model cannot be gener- [3] Schindler C, Darnell JE jr. Transcriptional responses to polypep-
tide ligands: The JAK-STAT pathway. Annu Rev Biochem 1995;
alized to humans. 64: 62151.
The activation of the JAK-STAT pathway is supposed to [4] Heinrich PC, Behrmann I, Mller-Newen G, Schaper F, Graeve L.
play important roles in the pathogenesis of myocardial hy- Interleukin-6 type cytokine signalling through the gp130/JAK/
pertrophy. Several findings indicate that hypertrophic agonists STAT pathway. Biochem J 1998; 334: 297314.
(e.g. leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), [5] Darnell JE jr. STATs and gene regulation. Science 1997; 277:
angiotensin II) induce the JAK-STAT system in vitro [8082]. 16305.
[6] Yeh TC, Pellegrini S. The Janus kinase family of protein tyrosine
Acute pressure overload in vivo activated the JAK-STAT path- kinases and their role in signaling. Cell Mol Life Sci 1999; 55:
way [83]. Mechanical stretch, resembling the pathophysiology 152334.
of myocardial hypertrophy, activates the JAK-STAT pathway [7] Decker T, Kovarik P. Transcription factor activity of STAT pro-
in rat cardiomyocytes, this activation depends in part on the teins: structural requirements and regulation by phosphorylation
autocrine/paracrine secreted angiotensin II, but IL-6 type and interacting proteins. Cell Mol Life Sci 1999; 55: 153546.
cytokines were found to be primarily responsible for the induc- [8] Wen Z, Zhong Z, Darnell JEJr. Maximal activation of transcription
by STAT1 and STAT3 requires both tyrosine and serine phospho-
tion of the JAK-STAT cascade [84]. rylation. Cell 1995; 82: 24150.
Constitutive activation of STAT1 has been described in [9] Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ,
the bronchial epithelial cells of asthma patients that correlat- Copeland NG et al. A novel cytokine-inducible gene CIS encodes
ed with the enhanced expression of ICAM-1 (intercellular an SH2-containing protein that binds to tyrosine-phosphorylated
adhesion molecule -1) that in turn could facilitate the recruit- interleukin 3 and erythropoietin receptors. EMBO J 1995; 14:
ment of T-cells to the sites of inflammation [85] (Table 5). 281626.
[10] Starr R, Willson TA, Viney EM, Murray LJL, Rayner JR, Jenkins
BJ et al. A family of cytokine-inducible inhibitors of signalling.
Nature 1997; 387: 91721.
Conclusions [11] Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mit-
sui K et al. A new protein containing an SH2 domain that inhibits
Although discovered only in the past decade, the JAK-STAT JAK kinases. Nature 1997; 387: 9214.
pathway showed an enormous career, being implicated in [12] Naka T, Narazati M, Hirata M, Matsumoto T, Minamoto S, Aono
A et al. Structure and function of a new STAT-induced STAT
the actions of numerous mediators (cytokines, growth fac- inhibitor. Nature 1997; 387: 92429.
tors, hormones). The JAK-STAT system participates in the [13] Hilton DJ, Richardson RT, Alexander WS, Viney EM, Willson TA,
regulation of both immune (inflammatory) and non-immune Sprigg NA et al. Twenty proteins containing a C-terminal SOCS
processes. Since several knockout models do not reach adult- box form five structural classes. Proc Natl Acad Sci USA 1998;
hood, the importance of the JAK-STAT system appears to 95: 1149.
extend beyond the immune system, and several basic phe- [14] Mui AL, Wakao H, Kinoshita T, Kitamura T, Miyajima A. Sup-
pression of interleukin-3-induced gene expression by a C-terminal
nomena (e.g. cell proliferation, apoptosis, differentiation) truncated Stat5: role of STAT5 in proliferation. EMBO J 1996; 15:
seem to require its correct functioning. In contrast to the 242533.
abundance of the in vitro data, the in vivo and clinical obser- [15] Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A,
vations are scarce, but considerable progress is to be expect- Wakioka T et al. The JAK-binding protein JAB inhibits Janus tyro-
ed in these fields too in the coming future. sine kinase activity through binding in the activation loop. EMBO
J 1999; 18: 130920.
[16] Nicholson SE, De Souza D, Fabri LJ, Corbin J, Willson TA, Zhang-
JG et al. Suppressor of cytokine signaling-3 preferentially binds to
Table 5. Summary of diseases that appear to be associated with the the SHP-2-binding site on the shared cytokine receptor subunit
malfunctioning of the JAK-STAT pathway. gp130. Proc Natl Acad Sci USA 2000; 97: 64938.
[17] Krebs DL, Hilton DJ. SOCS: physiological suppressors of
Disease Mechanisms Ref. cytokine signaling. J Cell Sci 2000; 113: 28139.
[18] Zhang JG, Farley A, Nicholson SE, Willson TA, Zugaro LM,
Leukemias/ fusion proteins, virus-induced [6372] Simpson RJ et al. The conserved SOCS box motif in suppressors
lymphomas JAK-STAT activation, STAT3 of cytokine-signalling binds to elongins B and C and may couple
overexpression, constitutive Ser bound proteins to proteosomal degradation. Proc Natl Acad Sci
phosphorylation of STAT proteins USA 1999; 96: 20716.
Tumors of the enhanced STAT expression [73,74] [19] Starr R, Hilton DJ. Negative regulation of the JAK/STAT pathway.
head-neck region, Bioessays 1999; 21: 4752.
meningiomas [20] Kim H, Baumann H. Dual signaling role of the protein tyrosine
phophatase SHP-2 in regulating expression of acute-phase plasma
human SCID JAK3 and gc chain mutations [7578] protein by interleukin-6 cytokine receptors in hepatic cells. Mol
myocardial JAK-STAT activation by mechanical [7984] Cell Biol 1999; 19: 532638.
hypertrophy stretch, pressure overload [21] Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD et al.
bronchial asthma increased epithelial expression of STAT1 [85] Inhibition of STAT1-mediated gene activation by PIAS1. Proc
Natl Acad Sci USA 1998;95:10626-31.
440 P. Igaz et al. Inflamm. res.

[22] Hilton DJ. Negative regulators of cytokine signal transduction. gland development and lactogenesis. Genes Dev 1997; 11:
Cell Mol Life Sci 1999; 55: 156877. 17986.
[23] Rodig S, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD [44] Wakao H, Gouilleux F, Groner B. Mammary gland factor (MGF)
et al. Disruption of the JAK1 gene demonstrates obligatory and is a novel member of the cytokine regulated transcription factor
non redundant roles of the JAKs in cytokine-induced biologic gene family and confers the prolactin response. EMBO J 1994; 13:
responses. Cell 1998; 93: 37383. 218291.
[24] Parganas E, Warg D, Stravopodis D, Topham D, Marine JC, [45] Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA et al.
Teglund DJ et al. JAK2 is essential for signaling through a variety Requirement of STAT5b for sexual dimorphism of body growth
of cytokine receptors. Cell 1998; 93: 38595. rates and liver gene expression. Proc Natl Acad Sci USA; 94:
[25] Neubauer H, Cumano A, Mller M, Wu H, Hufffstadt U, Pfeffer K. 723944.
JAK2 deficiency defines an essential developmental checkpoint in [46] Nakajima H, Liu XW, Wynshaw-Boris A, Rosenthal LA, Imada K,
definitive hematopoiesis. Cell 1998; 93: 397409. Finbloom DS et al. An indirect effect of STAT5a in IL-2 induced
[26] Nosaka T, van Deursen JM, Tripp RA, Thierfelder WE, Witthuhn proliferation: a critical role for STAT5a in IL-2-mediated IL-2
BA, McMickle AP et al. Defective lymphoid development in mice receptor alpha chain induction. Immunity 1997; 7: 691701.
lacking Jak3. Science 1995; 270: 8002. [47] Imada K, Bloom ET, Nakajima H, Horvath-Arcidianoco JA, Udy
[27] Park SY, Saijo K, Takahashi T, Osawa M, Arase H, Hirayama N et GB, Davey HW et al. Stat5b is essential for natural killer cell-
al. Developmental defects of lymphoid cells in Jak3 kinase-defi- mediated proliferation and cytolytic activity. J Exp Med 1998;
cient mice. Immunity 1995; 3: 77182. 188: 206774.
[28] Thomis DC, Berg LJ. The role of JAK3 in lymphoid development. [48] Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D,
activation and signalling. Curr Opin Immunol 1997; 9: 5417. Wang D et al. Stat5a and Stat5b proteins have essential and
[29] Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL et al. Defec- nonessential, or redundant roles in cytokine responses. Cell 1998;
tive lymphoid development in mice lacking expression of the com- 93: 84150.
mon cytokine receptor g chain. Immunity 1995; 2: 22338. [49] Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C, Wang D et
[30] DiSanto JP, Mller W, Guy-Grand D, Fischer A, Rajewsky K. al. STAT5 is required for IL-2-induced cell cycle progression of
Lymphoid development in mice with a targeted deletion of the peripheral T cells. Immunity 1999; 10: 24959.
interleukin-2 receptor g chain. Proc Natl Acad Sci USA 1995; 92: [50] Starr R, Metcalf D, Elefanty AG, Brysha M, Willson TA, Nicola
37781. NA et al. Liver degeneration and lymphoid deficiencies in mice
[31] Sugamura K, Asao H, Kondo M, Tanaka N, Ishii N, Ohbo K et al. lacking suppressor of cytokine signaling-1. Proc Natl Acad Sci
The interleukin-2 receptor gamma chain: its role in the multiple USA 1998; 95: 143959.
cytokine receptor complexes and T cell development in XSCID. [51] Metcalf D, Alexander WS, Elefanty AG, Nicola NA, Hilton DJ,
Annu Rev Immunol 1996; 14: 179205. Starr R et al. Aberrant hematopoiesis in mice with inactivation of
[32] Durbin JE, Hackenmiller R, Simon MC, Levy DE. Targeted dis- the gene encoding SOCS-1. Leukemia 1999; 13: 92634.
ruption of the mouse STAT1 gene results in compromised innate [52] Marine JC, Topham DJ, McKay C, Wang D, Parganas E,
immunity to viral disease. Cell 1996; 84: 44350. Stravopodis D et al. SOCS1 deficiency causes a lymphocyte-
[33] Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe dependent perinatal lethality. Cell 1999; 98: 60916.
AS et al. Targeted disruption of the Stat1 gene in mice reveals [53] Naka T, Matsumoto T, Narazaki M, Fujimoto M, Morita Y, Ohsawa
unexpected physiologic specificity in the JAK-STAT signaling Y et al. Accelerated apoptosis of lymphocytes by augmented
pathway. Cell 1996; 84: 43142. induction Bax in SSI-1 (STAT-induced STAT inhibitor-1) defi-
[34] Park C, Li S, Cha E, Schindler C. Immune response in Stat2 cient mice. Proc Natl Acad Sci USA 1998; 95: 1557782.
knockout mice. Immunity 2000;13:795-804. [54] Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg
[35] Levy DE. Physiological significance of STAT proteins: investiga- NS et al. SOCS1 is a critical inhibitor of interferon g signaling and
tion through gene disruption in vivo. Cell Mol Life Sci 1999; 55: prevents the potentially fatal neonatal actions of this cytokine. Cell
156877. 1999; 98:5 97608.
[36] Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto T, Yoshida N [55] Gresser L, Aguet M, Morel-Maroger L, Woodrow D, Puvion-
et al. Targeted disruption of the mouse STAT3 gene leads to early Dutilleul F, Guillon JC et al. Electrophoretically pure mouse
embryonic lethality. Proc Natl Acad Sci USA 1997; 94: 38014. interferon inhibits growth, induces liver and kidney lesions, and
[37] Mui ALF. The role of STATs in proliferation, differentiation and kissl suckling mice. Am J Pathol 1981; 102: 396402.
apoptosis. Cell Mol Life Sci 1999; 55: 154758. [56] Metcalf D, DiRago L, Mifsud S, Hartley L, Alexander WS. The
[38] DeFraja C, Conti L, Magrassi L, Govoni S, Cattaneo E. Members development of fatal myocarditis and polymyositis in mice het-
of the JAK/STAT proteins are expressed and regulated during erozygous for IFN-g and lacking the SOCS1 gene. Proc Natl Acad
development in the mammalian forebrain. J Neurosci Res 1998; Sci USA 2000; 97: 91749.
54: 32030. [57] Alexander WS, Starr R, Metcalf D, Nicholson SE, Farley A, Ele-
[39] Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 fanty AG et al. Suppressors of cytokine signalling (SOCS): negative
responses and enhanced development of Th2 cells in STAT4 defi- regulators of signal transduction. J Leukoc Biol 1999; 66: 58892.
cient mice. Nature 1997; 382: 1747. [58] Metcalf D, Greenhalgh CJ, Viney E, Willson TA, Starr R, Nicola
[40] Thierfelder WE, Deursen J, Yamamoto K, Tripp R, Sarawar SR, NA et al. Gigantism in mice lacking suppressor of cytokine sig-
Carson RT et al. Requirement for STAT4 in interleukin 12 medi- nalling-2. Nature 2000; 405: 106973.
ated responses of natural killer and T cells. Nature 1996; 382: [59] Marine JC, McKay C, Wang D, Topham DJ, Parganas E, Nakajima
1714. H et al. SOCS3 is essential in the regulation of fetal liver erythro-
[41] Kuperman D, Schofield B, Wills-Karp M, Grusby MJ. Signal poiesis. Cell 1999; 98: 61727.
transducer and activator of transcription factor 6 (STAT6)-defi- [60] Schultz LD, Schweitzer PA, Rajan TV, Yi T, Ihle JN, Mathews RJ
cient mice are protected from antigen-induced airway hyperre- et al. Mutation at the murine motheaten locus are within the
sponsiveness and mucus protection. J Exp Med 1998; 187: hematopoietic cell protein-tyrosine phophatase (Hcph) gene. Cell
93948. 1993; 73: 144554.
[42] Akimoto T, Numata F, Tamura M, Takata Y, Higashida N, Takashi [61] Qu CK, Yu WM, Azzarelli B, Feng GS. Genetic evidence that
T et al. Abrogation of bronchial eosinophilic inflammation and air- SHP-2 tyrosine phosphatase is a signal enhancer of epidermal
way hyperreactivity in signal transducers and activators of tran- growth factor receptor in mammals. Proc Natl Acad Sci USA
scription (STAT)6-deficient mice. J Exp Med 1998; 187: 1999; 96: 852833.
153742. [62] Fearson JA, Alexander DR. The role of phosphotyrosine phos-
[43] Liu X, Robinson GW, Wagner KU, Garrett L, Wyneshaw-Boris A, phatases in haemopoietic cell signal transduction. Bioessays 1997;
Henninghausen L. STAT5a is mandatory for adult mammary 19: 41727.
Vol. 50, 2001 Significance of the JAK-STAT pathway 441

[63] Lacronique V, Boureux A, Della Valle V, Poirel H, Tran Quang C, [73] Bromberg JF, Wrzeszczynska MH, Dergan G, Zhao Y, Pestell RG,
Mauchauff M et al. A Tel-JAK2 fusion protein with constitutive Albanese C et al. STAT3 as an oncogene. Cell 1999; 98: 295303.
kinase activity in human leukemia. Science 1997; 278: 130912. [74] Magrassi L, DeFraja C, Conti L, Butti G, Infuso L, Govoni S et al.
[64] Takemoto S, Malloy JC, Cereseto A, Migone TS, Patel BK, Mat- Expression of the JAK and STAT superfamilies in human menin-
suoka M et al. Proliferation of adult T cell leukemia/lymphoma giomas. J Neurosci 1999; 91: 4406.
cells is associated with constitutive activation of JAK/STAT pro- [75] Malek TR, Porter BO, He YW. Multiple gc-dependent cytokines
tein. Proc Natl Acad Sci USA 1997; 94: 13897902. regulate T-cell development. Immunol Today 1999; 20: 716.
[65] Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitz- [76] Macchi P, Villa A, Gillani S, Sacco MG, Frattini A, Porta F et al.
ki D, Savino R et al. Constitutive activation of STAT3 signaling Mutations of the Jak-3 gene in patients with autosomal severe
confers resistance to apoptosis in human U266 myeloma cells. combined immune deficiency (SCID). Nature 1995; 377: 658.
Immunity 1999; 10: 10515. [77] Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman
[66] Nielsen M, Kaestel CG, Eriksen KW, Woetmann A, Stokkedal T, MJ et al. Mutation of Jak3 in a patient with SCID: essential role of
Kaltoft K et al. Inhibition of constitutively activated STAT3 corre- Jak3 in lymphoid development. Science 1995; 270: 797800.
lates with altered Bcl-2/Bax expression and induction of apoptosis [78] Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S,
in mycosis fungoides tumor cells. Leukemia 1999; 13: 7358. Modi WS et al. Interleukin-2 receptor g chain mutation results in
[67] Chai SK, Nichols GL, Rothman P. Constitutive activation of JAKs X-linked severe combined immunodeficiency in humans. Cell
and STATs in Bcr-Abl expressing cell lines and peripheral blood 1993; 73: 14757.
cells derived from leukemic patients. J Immunol 1997; 159: [79] Puel A, Ziegler SF, Buckley RH, Leonard WJ. Defective IL7R
47208. gene expression in TB+NK+ severe combined immunodeficiency.
[68] Zhang Q, Nowak L, Vonderheid EC, Rook AH, Kadin ME, Now- Nat Genet 1998; 20: 3947.
ell PC et al. Activation of JAK/STAT proteins involved in signal [80] Kunisada K, Hirota H, Fujio Y, Matsui H, Tani Y, Yamauchi-Taki-
transduction pathway mediated by receptor for interleukin 2 in hara K et al. Activation of JAK-STAT and MAP kinases by
malignant T lymphocytes derived from cutaneous anaplastic large leukemia inhibitory factor through gp130 in cardiac myocytes.
T-cell lymphoma and Sezary syndrome. Proc Natl Acad Sci USA Circulation 1998; 94: 262632.
1996; 93: 914853. [81] Pennica D, Wood WI, Chien KR. Cardiotrophin-1: a multifunc-
[69] Hayakawa F, Towatasi M, Iida H, Wakao H, Kiyos H, Naoe T et al. tional cytokine that signals via LIF receptor-gp130 dependent
Differential constitutive activation between STAT-related proteins pathways. Cytokine Growth Factor Rev 1996; 7: 8191.
and MAP kinase in primary acute myelogenous leukemia. Br J [82] Kodama H, Fukuda K, Pan J, Makino S, Sano M, Takahashi T et
Haematol 1998; 101: 5218. al. Biphasic activation of the JAK/STAT pathway by angiotensin II
[70] Liu RY, Fan C, Garcia R, Jove R, Zuckerman KS. Constitutive acti- in rat cardiomyocytes. Circ Res 1998; 82: 24450.
vation of the JAK2/STAT5 signal transduction pathway correlates [83] Pan J, Fukuda K, Kodama H, Makino S, Takahashi T, Sano M et al.
with growth factor independence of megakaryocytic leukemia cell Role of angiotensin II in activation of the JAK/STAT pathway
lines. Blood 1999; 93: 236979. induced by acute pressure overload in the rat heart. Circ Res 1997;
[71] Henderson YC, Guo XYD, Greenberger J, Deisreroth AB. Poten- 81: 6117.
tial role of Bcr-Abl in the activation of JAK1 kinase. Clin Cancer [84] Pan J, Fukuda K, Saito M, Matsuzaki J, Kodama H, Sano M et al.
Res 1997; 3: 1459. Mechanical stretch activates the JAK/STAT pathway in rat car-
[72] Frank DA, Mahajan S, Ritz J. B-lymphocytes from patients with diomyocytes. Circ Res 1999; 84: 112736.
chronic lymphocytic leukemia contain signal transducer and acti- [85] Sampath D, Castro M, Look DC, Holtzman MJ. Constitutive acti-
vator of transcription (STAT)1 and STAT3 constitutively phospho- vation of an epithelial signal transducer and activator of transcrip-
rylated on serine residues. J Clin Invest 1997; 100: 31408. tion (STAT) pathway in asthma. J Clin Invest 1999; 103: 135361.