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Concise Reviews |
Department of Biochemistry, CREST of Japan Science and Technology Corporation, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
Key Words. Cytokine • Signal transduction • STAT • JAK kinase • Cre-loxP system • Conditional knockout
Correspondence:
Dr. Shizuo Akira, Department of Biochemistry, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
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Abstract |
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 Top Abstract IntroductionSTAT1 Knockout (KO) MiceSTAT4 and STAT6 KO...STAT5a and STAT5b KO...STAT3 KO MiceConclusionReferences |
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Introduction |
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TopAbstractIntroductionSTAT1 Knockout (KO) MiceSTAT4 and STAT6 KO...STAT5a and STAT5b KO...STAT3 KO MiceConclusionReferences |
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STAT proteins are activated as follows ( Fig. 3): they are initially present in inactive forms in the cytoplasm, while Jak kinases are constitutively associated with the cytoplasmic membrane-proximal regions of various receptors. Upon ligand binding, Jak kinases become catalytically activated, and at the same time, tyrosine residues in the cytoplasmic domain of the receptor become phosphorylated. This phosphorylation leads to the recruitment of STAT proteins via recognition of the receptor phosphotyrosines by the STAT SH2 domains. The activated Jak kinases then phosphorylate STAT proteins at their tyrosine residues. Thereafter, the phosphorylated STAT proteins detach from the receptor, become homodimerized or heterodimerized, and translocate to the nucleus to activate transcription by interaction with specific DNA sequences. The selectivity of STAT activation by different ligands is determined mainly by the highly specific interactions between the SH2 domain of the respective STAT and the phosphotyrosine residues on each receptor. Although JAK kinases have not been shown to have any substrate specificities, they do have different, specific, biological functions, as demonstrated in vivo by gene targeting studies [8-10].
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In addition to the tyrosine phosphorylation required for both dimerization and translocation to the nucleus, STAT proteins also require serine phosphorylation for transcriptional activation [17, 18]. The carboxy-terminal regions of STAT1, STAT3, STAT4, and STAT5 contain the MAPK consensus phosphorylation sequence, although there is no evidence showing that MAPKs are actually involved in the serine phosphorylation of STATs in vivo.
In most cases, STAT activation is transient. Inactivation of STAT proteins is carried out by several mechanisms, including dephosphorylation of STAT proteins in the nucleus and degradation through the ubiquitin-proteasome pathway [19]. A novel family of negative feedback inhibitors of the JAK-STAT pathway has recently been identified, referred to as suppressor-of-cytokine-signaling (SOCS) proteins/Jak-binding (JAB) proteins, and /STAT-induced STAT inhibitors (SSIs) [20-22]. These proteins contain the SH2 domain, and expression of each is induced by cytokine stimulation. Each member of the family interacts with the kinase domain (JH1) of various JAKs or the cytoplasmic phosphotyrosine residue of the relevant receptor, which results in the inhibition of STAT protein phosphorylation. In addition, a family of protein inhibitors of activated STAT (PIAS) proteins has been isolated [23, 24]. PIAS3 associates with phosphorylated, but not unphosphorylated STAT3. PIAS3 blocks the DNA-binding activity of STAT3 and inhibits STAT3-mediated gene activation. Similarly, PIAS1 blocks the DNA-binding activity of STAT1 and inhibits STAT1-mediated gene activation. These findings suggest the possible existence of specific PIAS inhibitors for each STAT signaling pathway. Thus, it seems that the overall strength of STAT signaling for any given cell type may be largely influenced by the relative levels of STAT and PIAS protein expression.
Cytokines exert proliferative and antiproliferative responses depending on the cell type. The potential role of the STAT signaling pathway in cell cycle control and apoptosis has been investigated by a number of laboratories. STAT1 protein was shown to be essential for cell growth suppression in response to interferon-
(IFN-). In the case of STAT1-deficient U3A cells, IFN- did not inhibit growth of the parental line but did inhibit the growth of U3A cells into which STAT1 was reintroduced. The molecular mechanism mediating this growth inhibition involves the regulation of the gene encoding the cyclin-dependent kinase inhibitor p21 WAF1/CIP1 by STAT1 [25]. STAT4 and 6 proteins are shown to mediate the cytokine-induced proliferative responses of activated T cells by downregulating the expression of the cell cycle inhibitor p27Kip1, allowing cyclin-cdk complexes to promote the G1 to the S phase transition of the cell cycle [26]. EGF and IFN- induce apoptosis in certain cell lines, and both EGF- and IFN--induced apoptosis are effectively blocked by the addition of Z-Val-Ala-Asp-fluoromethylketone. In such cells, STAT1 activation induces apoptosis through the induction of the gene encoding caspase 1 (interleukin-1ß converting enzyme, [ICE]) [27, 28].
Increasing evidence suggests a link between STAT activation and oncogenic transformation. STAT proteins are constitutively activated in cells infected with human T-cell lymphotropic virus type I (HTLV-I) [29], abl/myc viruses [30], and spleen focus-forming virus [31]. STAT3 is constitutively activated in cells transformed by the v-Src [32-34], v-Abl [35], and BCR-ABL [36] oncoproteins, as well as in peripheral blood cells from acute leukemia patients and in tumor cells obtained from mycosis fungoides patients [37, 38]. STAT1 activation has been associated with the transformed state induced by v-Eyk [39]. TGF-
/EGF-R-mediated autocrine growth of transformed epithelial cells has been shown to be dependent on activation of STAT3 [40].
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STAT1 Knockout (KO) Mice |
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TopAbstractIntroductionSTAT1 Knockout (KO) MiceSTAT4 and STAT6 KO...STAT5a and STAT5b KO...STAT3 KO MiceConclusionReferences |
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and IFN-ß) and Type-II (IFN-). Both IFN- and IFN-ß bind to the Type-I IFN receptor, whereas IFN- binds to the Type-II IFN receptor. Each type of IFN activates different combinations of STAT proteins [1]. In the case of IFN-/ß stimulation, both STAT1 and STAT2 are activated and consequently heterodimerize and translocate to the nucleus, where they associate with p48 to form a transcriptional complex, termed ISGF3. In contrast, IFN- triggers the tyrosine phosphorylation of STAT1 but not STAT2. Activated STAT1 forms homodimers and migrates to the nucleus, where it binds to GAS (-activated site) sequences present in many promoters activated by IFN-. Thus, the difference in the functional effects of IFN- /ß and IFN- is the consequence of differential activation of STAT1 and STAT2.
STAT1 has been reported to be activated by a number of other cytokines and growth factors, including growth hormone, interleukin 2 (IL-2), EGF, and angiotensin. Nevertheless, STAT1 KO mice exhibit selective signaling defects in their response to both Type-1 and Type-II IFNs [41, 42]. IFN-- and IFN--induced expression of major histocompatibility complex (MHC) class II protein, as well as interferon regulatory factor-1 (IRF-1), guanylate-binding protein 1 (GBP-1), the MHC class II transactivating protein (CIITA), and the complement protein C3 were absent or diminished in STAT1 KO mice. These mice were also highly sensitive to infection by microbial pathogens and viruses. In contrast, STAT1 KO mice responded normally to several other cytokines that activate STAT1. These results indicate that STAT1 plays an obligate and dedicated role in mediating IFN-dependent biological responses.
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STAT4 and STAT6 KO Mice |
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TopAbstractIntroductionSTAT1 Knockout (KO) MiceSTAT4 and STAT6 KO...STAT5a and STAT5b KO...STAT3 KO MiceConclusionReferences |
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, which mainly promote cellular immunity. On the other hand, Th2 cells produce IL-4, IL-5, IL-10, and IL-13, and mainly promote humoral immunity. The Th1 to Th2 balance determines the outcome of a wide variety of immune responses involving infectious, autoimmune, and allergic diseases [43]. Acquired resistance against intracellular bacteria is associated with the Th1 response, whereas resistance against helminths is achieved by the Th2 response. Autoimmune diseases such as multiple sclerosis and Crohn's disease are associated with an abnormally strong Th1 response, whereas allergic diseases seem to involve an abnormally strong Th2 response. Both Th1 and Th2 cells are derived from a common precursor cell named Th0, and their differentiation is regulated by cytokines: IL-12 stimulates the differentiation of Th0 to Th1 cells, whereas IL-4 regulates Th2 differentiation. These cytokines are produced in the early phase of infection: IL-12 derives from infected macrophages and IL-4 from basophils, mast cells, and CD4+NK1.1+ T cells.
STAT4 was cloned by both polymerase chain reaction approaches and low-stringency hybridization [44, 45]. Unlike other STATs, STAT4 expression is restricted to myeloid cells, thymus, and testes. A subsequent study showed that STAT4 is specifically phosphorylated in response to IL-12 [46]. STAT4 KO mice are viable and fertile, but their major IL-12-mediated functions are impaired, including increases in the production of IFN-, cellular proliferation, enhancement of natural killer cell cytotoxicity, and Th1 cell differentiation [47, 48]. These results demonstrate that STAT4 is essential for mediating responses to IL-12 ( Fig. 4).
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chain of the IL-4 receptor. STAT6 KO mice have defects in IL-4-mediated functions including induction of CD23 and MHC class II expression, immunoglobulin class switching to IgE, B- and T-cell proliferation, and Th2 cell development, demonstrating the essential role of STAT6 in IL-4 signaling ( Fig. 4) [50-52]. Infection by the helminth N. brasiliensis is known to generate a selective activation of Th2-type immune responses in mice. Production of Th2 cytokines such as IL-4, IL-5, and IL-10 following infection with this parasite was almost completely blocked in the STAT6 KO mice. Increases in serum IgE levels after N. brasiliensis infection were not detected in the mutant mice. IL-13-mediated functions are also impaired in STAT6 KO mice [53]. Stimulation of macrophages by IL-13 is known to cause morphological change and increased MHC class II expression. IL-13 decreases the nitric oxide production of activated macrophages. All of these IL-13-mediated functions are impaired in STAT6 KO mice, demonstrating the essential role of STAT6 in IL-13 signaling. The role of STAT6 in allergen-induced airway inflammation has recently been assessed using STAT6 KO mice [54, 55]. Repeated exposure of actively immunized C57BL/6 mice to ovalbumin (OVA) aerosol increased their levels of serum IgE, the number of eosinophils in bronchoalveolar lavage (BAL) fluid, and airway reactivity. In contrast, STAT6 KO C57BL/6 mice treated in the same fashion did not develop hyper IgE, eosinophilia in BAL, or airway hyper-responsiveness. In the case of STAT6 KO mice with a Balb/C background, the airway hyper-responsiveness and increases in the number of mucus-containing cells following exposure to OVA were completely abolished, but induction of eosinophilia was only partially blocked. This difference may be due to their genetic backgrounds. These findings indicate that STAT6 plays a crucial role in the pathogenesis of allergen-induced airway inflammation and that inhibition of this pathway by specific agents could provide a novel strategy for the treatment of allergic disorders.
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STAT5a and STAT5b KO Mice |
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TopAbstractIntroductionSTAT1 Knockout (KO) MiceSTAT4 and STAT6 KO...STAT5a and STAT5b KO...STAT3 KO MiceConclusionReferences |
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STAT5 consists of two highly related genes encoding STAT5a and STAT5b proteins, which are 96% similar at the amino acid level [57]. These proteins differ mainly at the carboxyl terminus and present distinct DNA-binding specificities due to a single amino acid difference in the DNA binding domain [58]. These two proteins probably regulate the expression of common as well as distinct genes. Furthermore, subtle differences in the tissue distribution of STAT5a and STAT5b mRNA have been reported. These differences may explain the distinct function of these two proteins as revealed by the gene targeting studies described below.
The function of STAT5a in mammopoiesis and lactogenesis was investigated in mice by gene targeting. STAT5a KO mice developed normally and were indistinguishable from wild-type litter mates in size, weight, and fertility. However, mammary lobuloalveolar outgrowth during pregnancy was curtailed, and female mice failed to lactate after parturition due to a failure of the terminal differentiation of mammary gland [59]. These results demonstrate that STAT5a is the principal and an obligate mediator of mammopoietic and lactogenic signaling.
STAT5b KO mice have been generated. Disruption of the STAT5b gene was found to lead to the major loss of multiple responses associated with the sexually dimorphic pattern of pituitary growth hormone secretion. In the case of STAT5b KO males, body growth rates and male-specific liver gene expression were decreased to the levels observed in wild-type females, while female-predominant liver gene products were increased to a level intermediate to those of wild-type male and female levels [60]. Thus, STAT5b mediates the sexual dimorphic effects of GH pulses in liver and other target tissues. A recent study analyzing mice which lack STAT5a and/or STAT5b gene confirmed these findings [61]. In addition, STAT5a/b KO mice were found to have a defect in the development of functional corporal lutea in the ovary, resulting in female infertility. Female infertility is not observed in the STAT5a or STAT5b KO mice, demonstrating the functional redundancy of the STAT5 proteins.
The role of STAT5 in the immune system was also analyzed. Splenocytes from STAT5a KO mice have a partial defect in anti-CD3-induced proliferation that can be overcome by high doses of IL-2 [62]. This is because STAT5a activation is responsible for IL-2-induced IL-2R expression in T lymphocytes. Although IL-2R expression is also defective in STAT5b KO mice, it cannot be corrected by administration of high doses of IL-2. Splenocytes from STAT5b KO mice exhibited greatly diminished proliferation in response to IL-2 and IL-15. Basal as well as IL-2- and IL-15-mediated augmentation of natural killer (NK) cytolytic activity was also greatly diminished. The percentage of NK cells expressing IL-2Rß as well as the levels of IL-2- and IL-15-induced perforin expression in splenocytes were significantly diminished in STAT5b KO mice. These data indicate that STAT5b is essential for potent NK-cell-mediated proliferation and cytolytic activity [63]. In addition, bone marrow-derived macrophages from STAT5a KO mice have a defect in GM-CSF-induced proliferation as well as expression of GM-CSF-dependent genes such as CIS and a bcl-2 like gene A1 [64].
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STAT3 KO Mice |
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TopAbstractIntroductionSTAT1 Knockout (KO) MiceSTAT4 and STAT6 KO...STAT5a and STAT5b KO...STAT3 KO MiceConclusionReferences |
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, and IFN-) and IL-2 (IL-2, IL-7, and IL-15) families [68]. These receptor molecules harbor a common STAT3 docking motif (YxxQ) in their cytoplasmic domain [69]. STAT3 activity is detected during early postimplantation development in the mouse, suggesting that STAT3 plays a role during early embryogenesis [70]. In fact, STAT3-deficient mice die early in embryogenesis, prior to gastrulation [71]. By 7.5 days post-coitum, STAT3 RNA is expressed in the extraembryonic visceral endoderm, which is the principal site of nutrient exchange between the maternal and embryonic environments. The timing of the degeneration of STAT3-/- embryos coincides with the onset of STAT3 expression in visceral endoderm in wild-type mice, suggesting that STAT3-/- lethality may be due to a defect in visceral endoderm function, such as nutritional insufficiency. The ligand that activates STAT3 in visceral endoderm remains unknown.
The role of STAT3 has also been investigated using the dominant-negative STAT3 mutant (STAT3DN). In myeloid leukemic M1 cells, overexpression of STAT3DN abolished the differentiation response to IL-6 or LIF, indicating that STAT3 activation is essential for IL-6 or LIF-mediated growth arrest and differentiation of M1 cells [72, 73]. Embryonic stem (ES) cells are nontransformed stem cells that can be continuously propagated in vitro in the presence of LIF. ES clones constitutively expressing STAT3DN showed an increased tendency to differentiate [74]. Expression of STAT3DN using an inducible promoter in ES cells growing in the presence of LIF specifically abrogated self-renewal and promoted differentiation [75]. These data show that self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Although STAT1 can be activated in response to LIF in ES cells, STAT1 cannot compensate for STAT3, demonstrating that STAT3 has a specific and nonredundant function in ES cells.
STAT3 activation has further been shown to mediate IL-6- or LIF-induced astrocytic differentiation of primary cortical neuroepithelial cells [76]. It has also been shown that STAT3 is activated by hepatocyte growth factor and mediates epithelial tubulogenesis [77].
As described above, STAT3-deficient mice die during early embryogenesis. In an attempt to assess the role of STAT3 in adult tissues, we utilized the Cre-loxP recombination system, in which a specific region of DNA flanked by loxP sites can be deleted by expression of the Cre protein. We first generated floxed-STAT3 mice, in which two loxP sites were introduced, 5' and 3' of the exon encoding the tyrosine residue critical for STAT activation. Floxed-STAT3 mice were mated with transgenic mice expressing Cre protein in specific tissues. For T-cell-specific deletion, we used transgenic mice expressing Cre protein specifically in T cells under the control of the Lck promoter. STAT3-deficient T cells displayed a severely impaired proliferative response to IL-6 due to a defect in IL-6-mediated suppression of apoptosis. This result demonstrates the anti-apoptotic function of STAT3 [78]. STAT3-deficient T cells also show a partial defect in IL-2-induced proliferation owing to impaired IL-2-mediated IL-2R chain expression, as demonstrated in STAT5a-deficient T cells [79].
We have also generated mice in which STAT3 is deficient specifically in macrophages and neutrophils [80]. These mutant mice were highly susceptible to endotoxin shock and demonstrated increased production of inflammatory cytokines such as TNF-, IL-1, and IFN-. Production of inflammatory cytokines from STAT3-deficient macrophages is dramatically augmented in response to lipopolysaccharide. The mice also showed a polarized immune response of the Th1 type, as shown by increased secretion of IFN- from splenic T cells. Furthermore, the suppressive effects of IL-10 on cytokine production by macrophages and neutrophils were completely abolished. It was also found that aging mutant mice developed chronic enterocolitis. These results indicate that STAT3 functions in vivo in macrophages and neutrophils to signal anti-inflammatory responses mediated primarily by IL-10 ( Fig. 4).
The functional role of STAT3 in skin was assessed by crossing the floxed-STAT3 mice with mice expressing the Cre-transgene from the keratin 5 promoter. While development of the epidermis in these mutant mice was normal, skin wound healing was severely impaired. The motility of STAT3-deficient epidermal cells cultured in the presence of EGF or hemopoietic growth factor was also severely impaired in vitro, although proliferation was unaffected. This suggests that the defect in wound healing was due to the poor motility of epidermal cells (Sano S et al., submitted). Taken together, these analyses of tissue-specific STAT3-deficient mice demonstrate that STAT3 plays a crucial role in a variety of biological functions including cell growth, anti-apoptosis, and cell motility depending on the cell type and stimulus.
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Conclusion |
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TopAbstractIntroductionSTAT1 Knockout (KO) MiceSTAT4 and STAT6 KO...STAT5a and STAT5b KO...STAT3 KO MiceConclusionReferences |
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Acknowledgments |
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References |
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TopAbstractIntroductionSTAT1 Knockout (KO) MiceSTAT4 and STAT6 KO...STAT5a and STAT5b KO...STAT3 KO MiceConclusionReferences |
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chain induction. Immunity 1997;7:691.[Medline] chain expression in Stat3 deficient T lymphocytes. Int Immunol 1998;10:1747-1751.
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M. Benekli, M. R. Baer, H. Baumann, and M. Wetzler Signal transducer and activator of transcription proteins in leukemias Blood, April 15, 2003; 101(8): 2940 - 2954. [Abstract] [Full Text] [PDF]
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Y. Zhang, Y.-Y. Cho, B. L. Petersen, A. M. Bode, F. Zhu, and Z. Dong Ataxia Telangiectasia Mutated Proteins, MAPKs, and RSK2 Are Involved in the Phosphorylation of STAT3 J. Biol. Chem., April 4, 2003; 278(15): 12650 - 12659. [Abstract] [Full Text] [PDF]
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 A. Chojnacki, T. Shimazaki, C. Gregg, G. Weinmaster, and S. Weiss Glycoprotein 130 Signaling Regulates Notch1 Expression and Activation in the Self-Renewal of Mammalian Forebrain Neural Stem Cells J. Neurosci., March 1, 2003; 23(5): 1730 - 1741. [Abstract] [Full Text] [PDF]
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T. Welte, S. S. M. Zhang, T. Wang, Z. Zhang, D. G. T. Hesslein, Z. Yin, A. Kano, Y. Iwamoto, E. Li, J. E. Craft, et al. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: A critical role of STAT3 in innate immunity PNAS, February 18, 2003; 100(4): 1879 - 1884. [Abstract] [Full Text] [PDF]
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A. Woetmann, J. Brockdorff, P. Lovato, M. Nielsen, V. Leick, K. Rieneck, A. Svejgaard, C. Geisler, and N. Odum Protein Phosphatase 2A (PP2A) Regulates Interleukin-4-mediated STAT6 Signaling J. Biol. Chem., January 24, 2003; 278(5): 2787 - 2791. [Abstract] [Full Text] [PDF]
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S. Alas and B. Bonavida Inhibition of Constitutive STAT3 Activity Sensitizes Resistant Non-Hodgkin's Lymphoma and Multiple Myeloma to Chemotherapeutic Drug-mediated Apoptosis Clin. Cancer Res., January 1, 2003; 9(1): 316 - 326. [Abstract] [Full Text] [PDF]
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J. Parrish-Novak, W. Xu, T. Brender, L. Yao, C. Jones, J. West, C. Brandt, L. Jelinek, K. Madden, P. A. McKernan, et al. Interleukins 19, 20, and 24 Signal through Two Distinct Receptor Complexes. DIFFERENCES IN RECEPTOR-LIGAND INTERACTIONS MEDIATE UNIQUE BIOLOGICAL FUNCTIONS J. Biol. Chem., November 27, 2002; 277(49): 47517 - 47523. [Abstract] [Full Text] [PDF]
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 M. Aube, M. Lafrance, C. Charbonneau, I. Goulet, and M. Carreau Hematopoietic Stem Cells from Fancc-/- Mice Have Lower Growth and Differentiation Potential in Response to Growth Factors Stem Cells, September 1, 2002; 20(5): 438 - 447. [Abstract] [Full Text] [PDF]
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K. D. Bunting, H. L. Bradley, T. S. Hawley, R. Moriggl, B. P. Sorrentino, and J. N. Ihle Reduced lymphomyeloid repopulating activity from adult bone marrow and fetal liver of mice lacking expression of STAT5 Blood, January 15, 2002; 99(2): 479 - 487. [Abstract] [Full Text] [PDF]
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 K. Fukuda, Y. Fujitsu, N. Kumagai, and T. Nishida Characterization of the Interleukin-4 Receptor Complex in Human Corneal Fibroblasts Invest. Ophthalmol. Vis. Sci., January 1, 2002; 43(1): 183 - 188. [Abstract] [Full Text] [PDF]
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M. L. Guzman, D. Upchurch, B. Grimes, D. S. Howard, D. A. Rizzieri, S. M. Luger, G. L. Phillips, and C. T. Jordan Expression of tumor-suppressor genes interferon regulatory factor 1 and death-associated protein kinase in primitive acute myelogenous leukemia cells Blood, April 1, 2001; 97(7): 2177 - 2179. [Abstract] [Full Text] [PDF]
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E. S. Park, H. Kim, J. M. Suh, S. J. Park, S. H. You, H. K. Chung, K. W. Lee, O-Y. Kwon, B. Y. Cho, Y. K. Kim, et al. Involvement of JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) in the Thyrotropin Signaling Pathway Mol. Endocrinol., May 1, 2000; 14(5): 662 - 670. [Abstract] [Full Text]
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C. Daniel, A. Salvekar, and U. Schindler A Gain-of-function Mutation in STAT6 J. Biol. Chem., May 5, 2000; 275(19): 14255 - 14259. [Abstract] [Full Text] [PDF]
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Y. Zhang, J. Turkson, C. Carter-Su, T. Smithgall, A. Levitzki, A. Kraker, J. J. Krolewski, P. Medveczky, and R. Jove Activation of Stat3 in v-Src-transformed Fibroblasts Requires Cooperation of Jak1 Kinase Activity J. Biol. Chem., August 4, 2000; 275(32): 24935 - 24944. [Abstract] [Full Text] [PDF]
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