Kegg Pathway: Jak-STAT signaling pathway

J Dairy Sci. 2009 Dec; 92(12): 6186-6191
Khatib H, Huang W, Mikheil D, Schutzkus V, Monson RL

Infertility is a major cause of dairy cow culling and economic loss. Signal transducer and activator of transcription (STAT) proteins are transcription factors that play an important role in fertility and early embryonic development, among many other functions. Previous studies have reported the association of several genes from the JAK/STAT signaling pathway with fertility traits in cattle. The STAT1 and STAT3 genes are members of this pathway and are known to interact with each other by forming a heterodimer complex that enters the nucleus and controls expression of specific genes. Thus, the objective of this study was to investigate the effects of the interactions between polymorphisms in these genes on fertilization and early embryonic survival rates using an in vitro fertilization system. A total of 7,519 oocytes, collected from 445 ovaries, were exposed to sperm and a total of 5,075 embryos were produced. Fertilization rate was calculated as the number of cleaved embryos at 48 h post-fertilization out of the total number of oocytes exposed to sperm. Early embryonic survival rate of embryos was calculated as the number of blastocysts on d 7 of development out of the total number of embryos cultured. Effects of ovary genotypes on fertilization and early embryonic survival rates were evaluated. Single-SNP analysis revealed a statistically significant association between SNP25402 in STAT3 and fertilization rate. Oocytes produced from ovaries with AA genotype showed a 0.701 fertilization rate versus 0.666 and 0.663 for oocytes produced from AC and CC ovaries, respectively. The interaction between STAT3 SNP (SNP19069/SNP25402) was highly significant for survival rate but not for fertilization rate. Also, the interaction between STAT1 SNP and SNP19069 was highly significant for survival rate. Genotype combinations found to promote fertilization and embryonic survival could be incorporated into breeding programs aimed at improving fertility performance in dairy cattle.

Int J Hematol. 2009 Nov 14;
Kanda J, Uchiyama T, Tomosugi N, Higuchi M, Uchiyama T, Kawabata H

Overproduction of hepcidin by interleukin-6 (IL-6) is considered to be the main factor responsible for the development of anemia in inflammatory conditions. Since oncostatin M (OSM), a member of the IL-6 family, plays an important role in immune and inflammatory responses, we assessed the effect of OSM on hepcidin expression, as well as that of leukemia inhibitory factor (LIF), another member of the IL-6 family. We found that hepcidin expression was markedly induced by OSM and LIF in a time- and dose-dependent manner in hepatoma cell lines, and this expression was induced independent of IL-6/IL-6 receptor signaling. Luciferase assay revealed that OSM and LIF stimulated a -1.3-kb hepcidin promoter. This effect was markedly reduced when the signal transducer and activator of transcription (STAT) site of the promoter was mutated, and was almost completely abolished in the presence of AG-490, a Janus kinase (JAK) inhibitor. Hence, the JAK/STAT pathway plays a major role in OSM- and LIF-induced activation of the hepcidin promoter. In conclusion, we demonstrated that OSM and LIF can induce hepcidin expression mainly through the JAK/STAT pathways. Further studies are warranted to evaluate the clinical significance of OSM and LIF in the development of anemia in various inflammatory diseases.

Metabolism. 2009 Nov 13;
Elam MB, Yellaturu C, Howell GE, Deng X, Cowan GS, Kumar P, Park EA, Hiler ML, Wilcox HG, Hughes TA, Cook GA, Raghow R

We compared hepatic expression of genes that regulate lipid biosynthesis and metabolic signaling in liver biopsy specimens from women who were undergoing gastric bypass surgery (GBP) for morbid obesity with that in women undergoing ventral hernia repair who had experienced massive weight loss (MWL) after prior GBP. Comprehensive metabolic profiles of morbidly obese (MO) (22 subjects) and MWL (9 subjects) were also compared. Analyses of gene expression in liver biopsies from MO and MWL were accomplished by Affymetrix microarray, real-time polymerase chain reaction, and Western blotting techniques. After GBP, MWL subjects had lost on average 102 lb as compared with MO subjects. This was accompanied by effective reversal of the dyslipidemia and insulin resistance that were present in MO. As compared with MWL, livers of MO subjects exhibited increased expression of sterol regulatory element binding protein (SREBP)-1c and its downstream lipogenic targets, fatty acid synthase and acetyl-coenzyme A-carboxylase-1. Livers of MO subjects also exhibited enhanced expression of suppressor of cytokine signaling-3 protein and attenuated Janus kinase signal transducer and activator of transcription (JAK/STAT) signaling. Consistent with these findings, we found that the human SREBP-1c promoter was positively regulated by insulin and negatively regulated by STAT3. These data support the hypothesis that suppressor of cytokine signaling-3-mediated attenuation of the STAT signaling pathway and resulting enhanced expression of SREBP-1c, a key regulator of de novo lipid biosynthesis, are mechanistically related to the development of hepatic insulin resistance and dyslipidemia in MO women.

Dev Biol. 2009 Nov 6;
Beebe K, Lee WC, Micchelli CA

Adult stem cells are the most primitive cells of a lineage and are distinguished by the properties of self-renewal and multipotency. Coordinated control of stem cell proliferation and multilineage differentiation is essential to ensure a steady output of differentiated daughter cells necessary to maintain tissue homeostasis. However, little is known about the signals that coordinate stem cell proliferation and daughter cell differentiation. Here we investigate the role of the conserved JAK/STAT signaling pathway in the Drosophila intestinal stem cell (ISC) lineage. We show first, that JAK/STAT signaling is normally active in both ISCs and their newly formed daughters, but not in terminally differentiated enteroendocrine (ee) cells or enterocyte (EC) cells. Second, analysis of ISC lineages shows that JAK/STAT signaling is necessary but not sufficient for daughter cell differentiation, indicating that competence to undergo multilineage differentiation depends upon JAK/STAT. Finally, our analysis reveals JAK/STAT signaling to be a potent regulator of ISC proliferation, but not ISC self-renewal. On the basis of these findings, we suggest a model in which JAK/STAT signaling coordinates the processes of stem cell proliferation with the competence of daughter cells to undergo multilineage differentiation, ensuring a robust cellular output in the lineage.

Clin Cancer Res. 2009 Nov 15; 15(22): 6891-900
Liu PC, Caulder E, Li J, Waeltz P, Margulis A, Wynn R, Becker-Pasha M, Li Y, Crowgey E, Hollis G, Haley P, Sparks RB, Combs AP, Rodgers JD, Burn TC, Vaddi K, Fridman JS

PURPOSE: Deregulation of the Janus kinase-signal transducers and activators of transcription (Jak-STAT) pathway is a hallmark for the Philadelphia chromosome-negative myeloproliferative diseases polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We tested the efficacy of a selective JAK1/2 inhibitor in cellular and in vivo models of JAK2-driven malignancy. EXPERIMENTAL DESIGN: A novel inhibitor of JAK1/2 was characterized using kinase assays. Cellular effects of this compound were measured in cell lines bearing the JAK2V617F or JAK1V658F mutation, and its antiproliferative activity against primary polycythemiavera patient cells was determined using clonogenic assays. Antineoplastic activity in vivo was determined using a JAK2V617F-driven xenograft model, and effects of the compound on survival, organomegaly, body weight, and disease-associated inflammatory markers were measured. RESULTS: INCB16562 potently inhibited proliferation of cell lines and primary cells from PV patients carrying the JAK2V617F or JAK1V658F mutation by blocking Jak-STAT signaling and inducing apoptosis. In vivo, INCB16562 reduced malignant cell burden, reversed splenomegaly and normalized splenic architecture, improved body weight gains, and extended survival in a model of JAK2V617F-driven hematologic malignancy. Moreover, these mice suffered from markedly elevated levels of inflammatory cytokines, similar to advanced myeloproliferative disease patients, which was reversed upon treatment. CONCLUSIONS: These data showed that administration of the dual JAK1/2 inhibitor INCB16562 reduces malignant cell burden, normalizes spleen size and architecture, suppresses inflammatory cytokines, improves weight gain, and extends survival in a rodent model of JAK2V617F-driven hematologic malignancy. Thus, selective inhibitors of JAK1 and JAK2 represent a novel therapy for the patients with myeloproliferative diseases and other neoplasms associated with JAK dysregulation.

Klin Onkol. 2009; 22(5): 223-7
Chovanec J, Bienertová-Vasků JA, Dostálová Z

BACKGROUND: Previously, the polymorphism-2548 G/A within the promoter of the leptin (LEP) gene was reported to be associated with overweight and obesity, the factors significantly associated to increased endometrial cancer risk. Leptin has been described to play an important role in signal transduction in endometrial cancer cells indicating that leptin promotes endometrial cancer growth and invasiveness and implicating the JAK/STAT and AKT pathways as critical mediators of leptin action. The aim of the study was to investigate the possible associations of LEP-2548 G/A polymorphism with endometrial cancer and its related traits. DESIGN: Using PCR with following restriction analysis, we studied 67 endometrial cancer cases (mean age 64.3 +/- 10.3 years) that were enrolled in the study along with 67 controls matched for age, BMI and ethnic origin (mean age 62.1 +/-9.8 years); an additional cohort of 543 healthy individual was recruited to investigate the general population frequencies. RESULTS:The present study revealed no significant differences between the genotypes or alleles of investigated polymorphism for endometrial cancer risk or its related traits (age of menarche, menopause, number of spontaneous abortions in personal history or waiting time till the onset of the disease) among the groups, thus indicating that the genetic variants of LEP-2548 G/A is not a relevant marker of endometrial cancer risk in this Czech population. Conclusions:To conclude, the polymorphism LEP-2548 G/A doesn't seem to represent a major genetic marker for endometrial cancer in the studied Czech population; however, it was associated with obesity, which finding is in accordance with previous reports.

Bioinformatics. 2009 Oct 29;
Toni T, Stumpf MP

MOTIVATION: Computer simulations have become an important tool across the biomedical sciences and beyond. For many important problems several different models or hypotheses exist and choosing which one best describes reality or observed data is not straightforward. We therefore require suitable statistical tools that allow us to choose rationally between different mechanistic models of e.g. signal transduction or gene regulation networks. This is particularly challenging in systems biology where only a small number of molecular species can be assayed at any given time and all measurements are subject to measurement uncertainty. RESULTS: Here we develop such a model selection framework based on approximate Bayesian computation and employing sequential Monte Carlo sampling. We show that our approach can be applied across a wide range of biological scenarios, and we illustrate its use on real data describing influenza dynamics and the Jak-STAT signalling pathway. Bayesian model selection strikes a balance between the complexity of the simulation models and their ability to describe observed data. The present approach enables us to employ the whole formal apparatus to any system that can be (efficiently) simulated, even when exact likelihoods are computationally intractable. CONTACT: ttoni@imperial.ac.uk, m.stumpf@imperial.ac.uk SUPPLEMENTARY INFORMATION: Tutorial on ABC rejection and ABC SMC for parameter estimation and model selection. Derivation of ABC SMC model selection algorithms. Supplementary figures and datasets.

J Reprod Immunol. 2009 Oct 30;
Szekeres-Bartho J, Halasz M, Palkovics T

Progesterone is indispensable in creating a suitable endometrial environment for implantation, and also for the maintenance of pregnancy. Successful pregnancy depends on an appropriate maternal immune response to the fetus. Along with its endocrine effects, progesterone also acts as an "immunosteroid", by contributing to the establishment of a pregnancy protective immune milieu. Progesterone plays a role in uterine homing of NK cells and upregulates HLA-G gene expression, the ligand for NK inhibitory and activating receptors. At high concentrations, progesterone is a potent inducer of Th2-type cytokines as well as of LIF and M-CSF production by T cells. A protein called progesterone-induced blocking factor (PIBF), by inducing a Th2-dominant cytokine production mediates the immunological effects of progesterone. PIBF binds to a novel type of the IL-4 receptor and signals via the Jak/STAT pathway, to induce a number of genes, that not only affect the immune response, but might also play a role in trophoblast invasiveness.

Dev Cell. 2009 Oct; 17(4): 440-2
Merdes G, Paro R

The identities of cells, determined by differential gene expression, are heritably maintained by the antagonistic functions of Polycomb group (PcG) and Trithorax group proteins. Two recent papers shed new light on tumor suppressive functions of PcG by reporting direct silencing of the Notch and JAK/STAT signaling pathways in Drosophila melanogaster.

J Virol. 2009 Oct 21;
Defilippis VR, Alvarado D, Sali T, Rothenburg S, Früh K

Human cytomegalovirus (HCMV) is a member of the beta herpesvirus family that, unlike other herpesviruses, triggers a strong innate immune response in infected cells that includes transcription of the interferon beta gene via activation of interferon regulatory factor 3 (IRF3). IRF3 activation requires signaling from pattern recognition receptors that is initiated by their interaction with specific pathogen-associated molecules. Yet while IRF3-activating pathways are increasingly well-characterized, the cellular molecules involved in HCMV-mediated IRF3-dependent interferon beta transcription are virtually unknown. We undertook a systematic examination of new and established IRF3-terminal pathway components to identify those that are essential to HCMV-triggered IRF3 activation. We show here that IRF3 activation induced by HCMV infection involves the newly identified protein STING but, in contrast to infections with other herpesviruses, occurs independently of the adaptor molecule IPS-1. We also show that the protein DDX3 contributes to HCMV-triggered expression of interferon beta. Moreover, we identify Z-DNA binding protein 1 (ZBP1) as being both essential for IRF3 activation and interferon beta expression triggered by HCMV as well as being sufficient to enhance HCMV-stimulated interferon beta transcription and secretion. ZBP1 transcription was also found to be induced following exposure to HCMV in a JAK/STAT-dependent manner thus perhaps also contributing to a positive feedback signal. Finally, we show that constitutive overexpression of ZBP1 inhibits HCMV replication. ZBP1 was recently identified as a cytosolic pattern recognition receptor of double stranded DNA and thus we propose a model for HCMV-mediated IRF3 activation that involves HCMV-associated DNA as the principal innate immune activating pathogen-associated molecular pattern.

BMC Cancer. 2009; 9: 366
Li H, Ren Z, Kang X, Zhang L, Li X, Wang Y, Xue T, Shen Y, Liu Y

BACKGROUND: Aberrant activity of tyrosine-phosphorylated proteins is commonly associated with HCC metastasis. Cell signaling events driven by these proteins are implicated in numerous processes that alter cancer cell behavior. Exploring the activities and signaling pathways of these proteins in HCC metastasis may help in identifying new candidate molecules for HCC-targeted therapy. METHODS: Hep3B (a nonmetastatic HCC cell line) and MHCC97H (a highly metastatic HCC cell line) were used in this study, and the tyrosine-phosphorylated proteins expressed in these cell lines were profiled by a phosphoproteomics technique based on LC-MS/MS. Protein-protein interaction and functional clustering analyses were performed to determine the activities of the identified proteins and the signaling pathways closely related to HCC metastasis. RESULTS: In both cell lines, a total of 247 phosphotyrosine (pTyr) proteins containing 281 pTyr sites were identified without any stimulation. The involvement of almost 30% of these in liver or liver cancer has not been reported previously. Biological process clustering analysis indicated that pTyr proteins involved in cell motility, migration, protein autophosphorylation, cell-cell communication, and antiapoptosis functions were overexpressed during metastasis. pathway clustering analysis revealed that signaling pathways such as those involved in EGFR signaling, cytokine- and chemokine-mediated signal transduction, and the PI3K and Jak-STAT cascades were significantly activated during HCC metastasis. Moreover, noncanonical regulation of the JNK cascade might also provide new targets for HCC metastasis. After comparing the pTyr proteins that were differentially expressed during HCC cell metastasis, we selected FER, a nonreceptor tyrosine kinase, and validated its role in terms of both expression and function. The data confirmed that FER might play a critical role in the invasion and metastasis of HCC. CONCLUSION: The identification of pTyr proteins and signaling pathways associated with HCC metastasis could provide useful information for selecting new molecular intervention targets. Moreover, FER might serve as a novel drug target in future HCC therapy.

Arterioscler Thromb Vasc Biol. 2009 Oct 15;
Manea A, Irina Tanase L, Raicu M, Simionescu M

OBJECTIVE: Oxidative stress mediated by Nox1- and Nox4-based NADPH oxidase (Nox) plays a key role in vascular diseases. The molecular mechanisms involved in the regulation of Nox are not entirely elucidated. Because JAK/STAT regulates many genes linked to inflammation, cell proliferation, and differentiation, we questioned whether this pathway is involved in the regulation of Nox1 and Nox4 in human aortic smooth muscle cells (SMCs). METHODS AND RESULTS: Cultured SMCs were exposed to interferon gamma (IFNgamma) for 24 hours. Using lucigenin-enhanced chemiluminescence and dihydroethidium assays, real-time polymerase chain reaction, and Western blot analysis, we found that JAK/STAT inhibitors significantly diminished the IFNgamma-dependent upregulation of Nox activity, Nox1 and Nox4 expression. In silico analysis revealed the presence of highly conserved GAS elements within human Nox1, Nox4, p22phox, p47phox, and p67phox promoters. Transient overexpression of STAT1/STAT3 augmented the promoter activities of each subunit. JAK/STAT blockade reduced the Nox subunits transcription. Chromatin immunoprecipitation demonstrated the physical interaction of STAT1/STAT3 proteins with the predicted GAS elements from Nox1 and Nox4 promoters. CONCLUSIONS: JAK/STAT is a key regulator of Nox1 and Nox4 in human vascular SMCs. Inhibition of JAK/STAT pathway and the consequent Nox-dependent oxidative stress may be an efficient therapeutic strategy to reduce atherogenesis.

Immunity. 2009 Oct 16; 31(4): 539-50
Hu X, Ivashkiv LB

Interferon-gamma (IFN-gamma) is an important mediator of immunity and inflammation that utilizes the Jak-STAT signaling pathway to activate the STAT1 transcription factor. Many functions of IFN-gamma have been ascribed to direct STAT1-mediated induction of immune effector genes, but recently it has become clear that key IFN-gamma functions are mediated by cross-regulation of cellular responses to other cytokines and inflammatory factors. Here, we review mechanisms by which IFN-gamma and STAT1 regulate signaling by Toll-like receptors, inflammatory factors, tissue-destructive cytokines, anti-inflammatory cytokines, and cytokines that activate opposing STATs. These signaling mechanisms reveal insights about how IFN-gamma regulates macrophage activation, inflammation, tissue remodeling, and helper and regulatory T cell differentiation and how Th1 and Th17 cell responses are integrated in autoimmune diseases.

Hepatology. 2009 Aug 5;
Blechacz BR, Smoot RL, Bronk SF, Werneburg NW, Sirica AE, Gores GJ

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is one of the key signaling cascades in cholangiocarcinoma (CCA) cells, mediating their resistance to apoptosis. Our aim was to ascertain if sorafenib, a multikinase inhibitor, may also inhibit JAK/STAT signaling and, therefore, be efficacious for CCA. Sorafenib treatment of three human CCA cell lines resulted in Tyr(705) phospho-STAT3 dephosphorylation. Similar results were obtained with the Raf-kinase inhibitor ZM336372, suggesting sorafenib promotes Tyr(705) phospho-STAT3 dephosphorylation by inhibiting Raf-kinase activity. Sorafenib treatment enhanced an activating phosphorylation of the phosphatase SHP2. Consistent with this observation, small interfering RNA-mediated knockdown of phosphatase shatterproof 2 (SHP2) inhibited sorafenib-induced Tyr(705) phospho-STAT3 dephosphorylation. Sorafenib treatment also decreased the expression of Mcl-1 messenger RNA and protein, a STAT3 transcriptional target, as well as sensitizing CCA cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. In an orthotopic, syngeneic CCA model in rats, sorafenib displayed significant tumor suppression resulting in a survival benefit for treated animals. In this in vivo model, sorafenib also decreased tumor Tyr(705) STAT3 phosphorylation and increased tumor cell apoptosis. Conclusion: Sorafenib accelerates STAT3 dephosphorylation by stimulating phosphatase SHP2 activity, sensitizes CCA cells to TRAIL-mediated apoptosis, and is therapeutic in a syngeneic rat, orthotopic CCA model that mimics human disease. (HEPATOLOGY 2009.).

Int Rev Immunol. 2009; 28(5): 376-93
Zhou F

Viral products inhibit MHC class I antigen processing and presentation via three major pathways: inhibition of major histocompatibility complex (MHC) class I expression on cells, blockade of peptide trafficking and loading on MHC class I molecules, and inhibition of peptide generation in host cells. Viral products also interfere with IFN-gamma -mediated JAK/STAT signal transduction in cells. These results imply that viral proteins probably inhibit the function of IFN-gamma in MHC class I antigen presentation via inactivation of JAK/STAT signal transduction in host cells. Mechanisms of viral products to inhibit IFN-gamma -mediated MHC class I antigen presentation were summarized in this literature review.

Proc Natl Acad Sci U S A. 2009 Oct 20; 106(42): 17841-6
Souza-Neto JA, Sim S, Dimopoulos G

Here, we show that the major mosquito vector for dengue virus uses the Jak-STAT pathway to control virus infection. Dengue virus infection in Aedes aegypti mosquitoes activates the Jak-STAT immune signaling pathway. The mosquito's susceptibility to dengue virus infection increases when the Jak-STAT pathway is suppressed through RNAi depletion of its receptor Domeless (Dome) and the Janus kinase (Hop), whereas mosquitoes become more resistant to the virus when the negative regulator of the Jak-STAT pathway, PIAS, is silenced. The Jak-STAT pathway exerts its anti-dengue activity presumably through one or several STAT-regulated effectors. We have identified, and partially characterized, two Jak-STAT pathway-regulated and infection-responsive dengue virus restriction factors (DVRFs) that contain putative STAT-binding sites in their promoter regions. Our data suggest that the Jak-STAT pathway is part of the A. aegypti mosquito's anti-dengue defense and may act independently of the Toll pathway and the RNAi-mediated antiviral defenses.

Curr Top Microbiol Immunol. 2010; 338: 35-44
Muñoz-Jordán JL

Dengue virus is sensed in mammalian cells by Toll-like receptors and DExD/H box RNA helicases, triggering a Type 1 interferon response. Interferon acts upon infected and noninfected cells by stimulating the JAK/STAT signaling pathway resulting in the activation of interferon stimulated genes that lead cells toward the establishment of an antiviral response. The recognition of the importance of this rapid protective response should come with the realization that dengue virus would circumvent the interferon response to propagate in the host. There is recent, mounting evidence for mechanisms encoded by the dengue virus that weaken interferon signaling. Nonstructural proteins expressed separately or in replicon vectors block phosphorylation and down-regulate expression of major components of the JAK/STAT pathway, causing reduced activation of gene expression in response to IFNalpha/beta interferon. As our understanding of viral-host interaction increases, opportunities for improved biological models and therapeutics discovery arise.

Science. 2009 Oct 2; 326(5949): 153-6
Issigonis M, Tulina N, de Cuevas M, Brawley C, Sandler L, Matunis E

Adult stem cells often reside in local microenvironments, or niches. Although niches can contain multiple types of stem cells, the coordinate regulation of stem cell behavior is poorly understood. In the Drosophila testis, Janus kinase-signal transducer and activator of transcription (Jak-STAT) signaling is directly required for maintenance of the resident germline and somatic stem cells. We found that the Jak-STAT signaling target and inhibitor Suppressor of cytokine signaling 36E (SOCS36E) is required for germline stem cell maintenance. SOCS36E suppresses Jak-STAT signaling specifically in the somatic stem cells, preventing them from displacing neighboring germline stem cells in a manner that depends on the adhesion protein integrin. Thus, in niches housing multiple stem cell types, negative feedback loops can modulate signaling, preventing one stem cell population from outcompeting the other.

J Mol Cell Biol. 2009 Sep 30;
Lin G, Xu N, Xi R

Drosophila and mammalian intestinal stem cells (ISCs) share similarities in their regulatory mechanisms, with both requiring Wingless (Wg)/Wnt signaling for their self-renewal, although additional regulatory mechanisms are largely unknown. Here we report the identification of Unpaired as another paracrine signal from the muscular niche, which activates a canonical JAK/STAT signaling cascade in Drosophila ISCs to regulate ISC self-renewal and differentiation. We show that compromised JAK signaling causes ISC quiescence and loss, whereas signaling overactivation produces extra ISC-like and progenitor cells. Simultaneous disruption or activation of both JAK and Wg signaling in ISCs results in a stronger ISC loss or a greater expansion of ISC-like cells, respectively, than by altering either pathway alone, indicating that the two pathways function in parallel. Furthermore, we show that loss of JAK signaling causes blockage of enteroblast differentiation and reduced JAK signaling preferentially affects enteroendocrine (ee) cell differentiation. Conversely, JAK overactivation produces extra differentiated cells, especially ee cells. Together with the functional analysis with Notch (N), we suggest two separate roles of JAK/STAT signaling in Drosophila ISC lineages: it functions upstream of N, in parallel and cooperatively with Wg signaling to control ISC self-renewal; it also antagonizes with N activity to control the binary fate choice of intestinal progenitor cells.

Am J Physiol Cell Physiol. 2009 Oct 7;
Li R, Maminishkis A, Banzon T, Wan Q, Jalickee S, Chen S, Miller SS

The present experiments show that IFNgamma receptors are mainly localized to the basolateral membrane of human retinal pigment epithelium (RPE). Activation of these receptors in primary cultures of human fetal RPE inhibited cell proliferation and migration, decreased RPE mitochondrial membrane potential, altered transepithelial potential and resistance, and significantly increased transepithelial fluid absorption (JV). These effects are mediated through JAK/STAT and P38 MAPK signaling pathways. Second messenger signaling through cAMP/PKA and IRF-1 dependent production of nitric oxide/cGMP stimulated the cystic fibrosis transmembrane conductance regulator (CFTR) at the basolateral membrane and increased transepithelial fluid absorption. In vivo experiments using a rat model of retinal reattachment showed that IFNgamma applied to the anterior surface of the eye can remove extra fluid deposited in the extracellular or subretinal space (SRS) between the retinal photoreceptors and RPE. This removal was blocked by a combination of PKA and JAK/STAT pathway inhibitors injected into the SRS. These results demonstrate a protective role for IFNgamma in regulating retinal hydration across the outer-blood-retinal barrier in inflammatory disease processes and provide the basis for possible therapeutic interventions.