scholarly journals Interleukin-13 is a potent activator of JAK3 and STAT6 in cells expressing interleukin-2 receptor-γ and interleukin-4 receptor-α

1996 ◽  
Vol 319 (3) ◽  
pp. 865-872 ◽  
Author(s):  
M. Grazia MALABARBA ◽  
Hallgeir RUI ◽  
Harald H. J. DEUTSCH ◽  
Johanna CHUNG ◽  
Frank S. KALTHOFF ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Biological Effects ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Cell Types ◽  
Janus Kinase ◽  
Interleukin 4 ◽  
Surface Receptors ◽  
A Cell ◽  
In Cells

The lymphocyte growth factors interleukin-2 (IL2), IL4, IL7, IL9 and IL15 use the common IL2 receptor-γ (IL2Rγ) and activate the IL2Rγ-associated tyrosine kinase JAK3 (Janus kinase 3). IL13 is structurally related to IL4, competes with IL4 for binding to cell surface receptors and exhibits many similar biological effects. The molecular basis for this functional overlap between IL4 and IL13 has been attributed mainly to a shared use of the 140 kDa IL4Rα, since these cytokines appear to be uniquely different in that, according to several recent reports, IL13 does not recruit the IL2Rγ or JAK3. This notion has been supported by the identification of a novel 70 kDa IL13 receptor in certain IL13-responsive cell lines that lack IL2Rγ. The present study sheds new light on the issue of functional overlap between IL13 and IL4, by demonstrating for the first time that, in cells that express both IL2Rγ and IL4Rα, IL13 can mimic IL4-induced heterodimerization of IL2Rγ and IL4Rα, with consequent marked activation of JAK3 and the transcription factor STAT6 (IL4-STAT). Reconstitution experiments in BA/F3 cells showed that both cytokines require the simultaneous presence of IL4Rα and IL2Rγ to mediate JAK3 and proliferative responses, and analysis of 12 IL4Rα variants showed that IL4 and IL13 signals were equally affected by mutations of the cytoplasmic domain. We conclude that IL13 activates the IL2Rγ-associated JAK3 tyrosine kinase in appropriate cell types, and propose that IL13 is capable of interacting with multiple receptor subunits in a cell-dependent and combinatorial manner. Consequently, we predict that partial disruption of IL13 signal transduction also contributes to the severe combined immunodeficiency syndromes associated with inactivation of the IL2Rγ or JAK3 genes.

Structural Analysis of Janus Kinases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3863-3863
Author(s):  
Titus J. Boggon ◽  
Yiqun Li ◽  
Michael J. Eck
Keyword(s):  
Structural Information ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Selective Inhibition ◽  
Kinase Domain ◽  
Janus Kinase ◽  
Catalytically Active ◽  
Carboxy Terminal ◽  
Structural Insights ◽  
Kinase A

Abstract Janus Kinase 3 (Jak3) plays an essential role in hematopoietic signaling. Primarily expressed in B-, T- and Natural killer cells, it is activated through the γc chain of interleukin-2 like cytokine receptors (IL-2, -4, -7, -9, -15, -21). Deficiency of catalytically active Jak3 or disruption of the Jak3:IL-2γc interaction results in severe combined immunodeficiency (SCID). Jak3-deficient humans demonstrate defects restricted to the immune system, suggesting that selective inhibition of Jak3 catalytic activity or interruption of the Jak3:IL-2γc interaction are potentially exploitable strategies to achieve immunosuppression. Jak kinases contain four defined regions; a catalytically active carboxy-terminal kinase, a pseudo-kinase, a SH2-like region and a N-terminal Ferm domain. To date, no direct structural information has been reported for portions of any of the Jak family kinases. Structural studies are underway to define crystallographically the kinase domain of Jak3 and the Jak3-Ferm:IL-2γc interaction. Structural insights into the mechanism of Jak activation and routes to specific inhibition will be discussed.

scholarly journals IGF-1R Modulation of Acute GH-Induced STAT5 Signaling: Role of Protein Tyrosine Phosphatase Activity

2013 ◽  
Vol 27 (11) ◽  
pp. 1969-1979 ◽  
Author(s):  
Yujun Gan ◽  
Yue Zhang ◽  
Ashiya Buckels ◽  
Andrew J. Paterson ◽  
Jing Jiang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phosphatase Activity ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Protein Tyrosine ◽  
Primary Osteoblasts ◽  
Ptp 1B ◽  
In Cells

GH is a potent anabolic and metabolic factor that binds its cell surface receptor (GHR), activating the GHR-associated tyrosine kinase, Janus kinase 2, which phosphorylates and activates the latent transcription factor, signal transducer and activator of transcription 5 (STAT5). Some GH actions are mediated by the elaboration of IGF-1, which exerts effects by binding and activating the heterotetrameric tyrosine kinase growth factor receptor, IGF-1R. In addition to this GH-GHR-IGF-1-IGF-1R scheme, we have demonstrated in primary osteoblasts and in islet β-cells that then deletion or silencing of IGF-1R results in diminished GH-induced STAT5 phosphorylation, suggesting that the presence of IGF-1R may facilitate GH signaling. In this study, we explore potential roles for protein tyrosine phosphatase activity in modulating GH-induced signaling, comparing conditions in which IGF-1R is present or diminished. We confirm that in mouse primary osteoblasts harboring loxP sites flanking the IGF-1R gene, infection with an adenovirus that expresses the Cre recombinase results in IGF-1R deletion and diminished acute GH-induced STAT5 phosphorylation. Furthermore, we present a new model of IGF-1R silencing, in which expression of short hairpin RNA directed at IGF-1R greatly reduces IGF-1R abundance in LNCaP human prostate cancer cells. In both models, treatment with a chemical inhibitor of protein tyrosine phosphatase-1B (PTP-1B), but not one of src homology region 2 domain-containing phosphotase-1 (SHP-1) and SHP-2, reverses the loss of GH-induced STAT5 phosphorylation in cells lacking IGF-1R but has no effect in cells with intact IGF-1R. Furthermore, expression of either a dominant-negative PTP-1B or the PTP-1B-interacting inhibitory protein, constitutive photomorphogenesis 1, also rescues acute GH-induced STAT5 signaling in IGF-1R-deficient cells but has no effect in IGF-1R replete cells. By expressing a substrate-trapping mutant PTP-1B, we demonstrate that tyrosine phosphorylated Janus kinase-2 is a PTP-1B substrate only in cells lacking IGF-1R. Collectively, our data suggest that IGF-1R positively regulates acute GH signaling by preventing access of PTP-1B activity to Janus kinase 2 and thereby preventing PTP-1B-mediated suppression of GH-induced STAT5 activation.

Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2009-2018 ◽  
Author(s):  
Joseph L. Roberts ◽  
Andrea Lengi ◽  
Stephanie M. Brown ◽  
Min Chen ◽  
Yong-Jie Zhou ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Transplantation ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Janus Kinase ◽  
Cell Functions ◽  
Janus Kinase 3

Abstract We found 10 individuals from 7 unrelated families among 170 severe combined immunodeficiency (SCID) patients who exhibited 9 different Janus kinase 3 (JAK3) mutations. These included 3 missense and 2 nonsense mutations, 1 insertion, and 3 deletions. With the exception of 1 individual with persistence of transplacentally transferred maternal lymphocytes, all infants presented with a T–B+NK– phenotype. The patient mutations all resulted in abnormal B-cell Janus kinase 3 (JAK3)–dependent interleukin-2 (IL-2)–induced signal transducer and activator of transcription-5 (STAT5) phosphorylation. Additional analyses of mutations permitting protein expression revealed the N-terminal JH7 (del58A) and JH6 (D169E) domain mutations each inhibited receptor binding and catalytic activity, whereas the G589S JH2 mutation abrogated kinase activity but did not affect γc association. Nine of the 10 patients are currently alive from between 4 years and 18 years following stem cell transplantation, with all exhibiting normal T-cell function. Reconstitution of antibody function was noted in only 3 patients. Natural killer (NK) function was severely depressed at presentation in the 4 patients studied, whereas after transplantation the only individuals with normal NK lytic activity were patients 1 and 5. Hence, bone marrow transplantation is an effective means for reconstitution of T-cell immunity in this defect but is less successful for restoration of B-cell and NK cell functions.

scholarly journals Signaling Enzymes and Ion Channels Being Modulated by the Actin Cytoskeleton at the Plasma Membrane

2021 ◽  
Vol 22 (19) ◽  
pp. 10366
Author(s):  
Filip Vasilev ◽  
Yulia Ezhova ◽  
Jong Tai Chun
Keyword(s):  
Ion Channels ◽  
Cell Surface ◽  
Actin Cytoskeleton ◽  
Animal Species ◽  
Wide Spectrum ◽  
Cell Types ◽  
Fine Tuning ◽  
Signaling Proteins ◽  
Surface Receptors ◽  
A Cell

A cell should deal with the changing external environment or the neighboring cells. Inevitably, the cell surface receives and transduces a number of signals to produce apt responses. Typically, cell surface receptors are activated, and during this process, the subplasmalemmal actin cytoskeleton is often rearranged. An intriguing point is that some signaling enzymes and ion channels are physically associated with the actin cytoskeleton, raising the possibility that the subtle changes of the local actin cytoskeleton can, in turn, modulate the activities of these proteins. In this study, we reviewed the early and new experimental evidence supporting the notion of actin-regulated enzyme and ion channel activities in various cell types including the cells of immune response, neurons, oocytes, hepatocytes, and epithelial cells, with a special emphasis on the Ca2+ signaling pathway that depends on the synthesis of inositol 1,4,5-trisphosphate. Some of the features that are commonly found in diverse cells from a wide spectrum of the animal species suggest that fine-tuning of the activities of the enzymes and ion channels by the actin cytoskeleton may be an important strategy to inhibit or enhance the function of these signaling proteins.

Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia

Blood ◽  
2009 ◽  
Vol 113 (14) ◽  
pp. 3297-3306 ◽  
Author(s):  
Roman Crazzolara ◽  
Adam Cisterne ◽  
Marilyn Thien ◽  
John Hewson ◽  
Rana Baraz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Cycle Arrest ◽  
Established Disease ◽  
A Cell ◽  
In Cells

Abstract Despite advances in the treatment of acute lymphoblastic leukemia (ALL), the majority of children who relapse still die of ALL. Therefore, the development of more potent but less toxic drugs for the treatment of ALL is imperative. We investigated the effects of the mammalian target of rapamycin inhibitor, RAD001 (Everolimus), in a nonobese diabetic/severe combined immunodeficiency model of human childhood B-cell progenitor ALL. RAD001 treatment of established disease increased the median survival of mice from 21.3 days to 42.3 days (P < .02). RAD001 together with vincristine significantly increased survival compared with either treatment alone (P < .02). RAD001 induced a cell-cycle arrest in the G0/1 phase with associated dephosphorylation of the retinoblastoma protein, and reduced levels of cyclin-dependent kinases 4 and 6. Ultrastructure analysis demonstrated the presence of autophagy and limited apoptosis in cells of RAD001-treated animals. In contrast, cleaved poly(ADP-ribose) polymerase suggested apoptosis in cells from animals treated with vincristine or the combination of RAD001 and vincristine, but not in those receiving RAD001 alone. In conclusion, we have demonstrated activity of RAD001 in an in vivo leukemia model supporting further clinical development of target of rapamycin inhibitors for the treatment of patients with ALL.

Functional Role of Interleukin-4 (IL-4) and IL-7 in the Development of X-Linked Severe Combined Immunodeficiency

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 607-612 ◽  
Author(s):  
Satoru Kumaki ◽  
Naoto Ishii ◽  
Masayoshi Minegishi ◽  
Shigeru Tsuchiya ◽  
David Cosman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Combined Immunodeficiency ◽  
T Cell Development ◽  
Interleukin 2 ◽  
Cell Development ◽  
Interleukin 4 ◽  
Combined Immunodeficiency ◽  
Survival Signal

X-linked severe combined immunodeficiency (X-SCID) is characterized by an absent or diminished number of T cells and natural-killer (NK) cells with a normal or elevated number of B cells, and results from mutations of the γc chain. The γc chain is shared by interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors. Recently, a survival signal through the IL-7 receptor  (IL-7R) chain was shown to be important for T-cell development in mice and was suggested to contribute to the X-SCID phenotype. In the present study, we examined function of a mutant γc chain (A156V) isolated from an X-SCID patient and found that T cells expressing the mutant γc chain were selectively impaired in their responses to IL-4 or IL-7 compared with the wild-type γc chain expressing cells although responses to IL-2 or IL-15 were relatively maintained. The result shows that IL-4– and/or IL-7–induced signaling through the γc chain is critical for T-cell development and plays an important role in the development of the X-SCID phenotype.

scholarly journals Activation of an enhancer on the syndecan-1 gene is restricted to fibroblast growth factor family members in mesenchymal cells.

1997 ◽  
Vol 17 (6) ◽  
pp. 3210-3219 ◽  
Author(s):  
P Jaakkola ◽  
T Vihinen ◽  
A Määttä ◽  
M Jalkanen
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Mutational Analysis ◽  
Biological Effects ◽  
Protein A ◽  
Cell Types ◽  
Regulatory Elements ◽  
Tyrosine Kinase Receptor ◽  
Fibroblast Growth

Fibroblast growth factors (FGFs) induce a variety of biological effects on different cell types. They activate a number of genes, including immediate-early genes, such as the transcription factors Fos and Jun, which are also common targets for other tyrosine kinase receptor-activating growth factors. Here we describe a secondary far-upstream enhancer on the syndecan-1 gene that is activated only by members of the FGF family in NIH 3T3 cells, not by other receptor tyrosine kinase-activating growth factors (e.g., epidermal growth factor, platelet-derived growth factor, insulin-like growth factor, or serum). This FGF-inducible response element (FiRE) consists of a 170-bp array of five DNA motifs which bind two FGF-inducible Fos-Jun heterodimers, one inducible AP-2-related protein, a constitutively expressed upstream stimulatory factor, and one constitutive 46-kDa transcription factor. Mutational analysis showed that both AP-1 binding motifs are required, but not sufficient, for FiRE activation. Moreover, agents such as 12-O-tetradecanoylphorbol-13-acetate, okadaic acid, or forskolin, which are known to activate AP-1 complexes and AP-1-driven promoters, fail to activate FiRE. However, FiRE can be activated by the tyrosine kinase phosphatase inhibitor orthovanadate. Taken together, this data implies a differential activation of growth factor-initiated signaling on AP-1-driven regulatory elements.

scholarly journals Platelet-Derived Growth Factor Receptor Association with Na+/H+ Exchanger Regulatory Factor Potentiates Receptor Activity

2000 ◽  
Vol 20 (22) ◽  
pp. 8352-8363 ◽  
Author(s):  
Stuart Maudsley ◽  
A. Musa Zamah ◽  
Nadeem Rahman ◽  
Jeremy T. Blitzer ◽  
Louis M. Luttrell ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Intracellular Signaling ◽  
Pdz Domain ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Platelet Derived Growth Factor ◽  
Regulatory Factor ◽  
In Cells

ABSTRACT Platelet-derived growth factor (PDGF) is a potent mitogen for many cell types. The PDGF receptor (PDGFR) is a receptor tyrosine kinase that mediates the mitogenic effects of PDGF by binding to and/or phosphorylating a variety of intracellular signaling proteins upon PDGF-induced receptor dimerization. We show here that the Na+/H+ exchanger regulatory factor (NHERF; also known as EBP50), a protein not previously known to interact with the PDGFR, binds to the PDGFR carboxyl terminus (PDGFR-CT) with high affinity via a PDZ (PSD-95/Dlg/Z0-1 homology) domain-mediated interaction and potentiates PDGFR autophosphorylation and extracellular signal-regulated kinase (ERK) activation in cells. A point-mutated version of the PDGFR, with the terminal leucine changed to alanine (L1106A), cannot bind NHERF in vitro and is markedly impaired relative to the wild-type receptor with regard to PDGF-induced autophosphorylation and activation of ERK in cells. NHERF potentiation of PDGFR signaling depends on the capacity of NHERF to oligomerize. NHERF oligomerizes in vitro when bound with PDGFR-CT, and a truncated version of the first NHERF PDZ domain that can bind PDGFR-CT but which does not oligomerize reduces PDGFR tyrosine kinase activity when transiently overexpressed in cells. PDGFR activity in cells can also be regulated in a NHERF-dependent fashion by stimulation of the β2-adrenergic receptor, a known cellular binding partner for NHERF. These findings reveal that NHERF can directly bind to the PDGFR and potentiate PDGFR activity, thus elucidating both a novel mechanism by which PDGFR activity can be regulated and a new cellular role for the PDZ domain-containing adapter protein NHERF.

scholarly journals Kinase Inhibition as Treatment for Acute and Chronic Graft-Versus-Host Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Lukas M. Braun ◽  
Robert Zeiser
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Chronic Gvhd ◽  
Interleukin 2 ◽  
Janus Kinase ◽  
Kinase Inhibition ◽  
Hematopoietic Stem ◽  
Host Disease

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies via the donor immune system driven graft-versus-leukemia effect. However, the therapy is mainly limited by severe acute and chronic graft-versus-host disease (GvHD), both being life-threatening complications after allo-HCT. GvHD develops when donor T cells do not only recognize remaining tumor cells as foreign, but also the recipient’s tissue, leading to a severe inflammatory disease. Typical GvHD target organs include the skin, liver and intestinal tract. Currently all approved strategies for GvHD treatment are immunosuppressive therapies, with the first-line therapy being glucocorticoids. However, therapeutic options for glucocorticoid-refractory patients are still limited. Novel therapeutic approaches, which reduce GvHD severity while preserving GvL activity, are urgently needed. Targeting kinase activity with small molecule inhibitors has shown promising results in preclinical animal models and clinical trials. Well-studied kinase targets in GvHD include Rho-associated coiled-coil-containing kinase 2 (ROCK2), spleen tyrosine kinase (SYK), Bruton’s tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) to control B- and T-cell activation in acute and chronic GvHD. Janus Kinase 1 (JAK1) and 2 (JAK2) are among the most intensively studied kinases in GvHD due to their importance in cytokine production and inflammatory cell activation and migration. Here, we discuss the role of kinase inhibition as novel treatment strategies for acute and chronic GvHD after allo-HCT.

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