Dual Role of the Jak1 FERM and Kinase Domains in Cytokine Receptor Binding and in Stimulation-Dependent Jak Activation

Haan, Serge; Margue, Christiane; Engrand, Arnaud; Rolvering, Catherine; Leur, Hildegard Schmitz-Van de; Heinrich, Peter C.; Behrmann, Iris; Haan, Claude

doi:10.4049/jimmunol.180.2.998

Cited by 52 publications

(47 citation statements)

References 42 publications

(64 reference statements)

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“…Studies of IFN-g signaling were performed on cells overexpressing Jak1 or Jak2 lysine mutants and concluded on a hierarchical activation as well, with Jak2 playing the initiator role (36). The question was recently re-examined for IFN-g with the same mutants expressed at near-endogenous levels, and the data pointed, instead, to Jak1 as the initiator (37). These studies emphasized the impact of Jak expression level and indicated a certain degree of catalytic hierarchy between two juxtaposed Jaks.…”

Section: Discussionmentioning

confidence: 99%

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

Gakovic

Ragimbeau

et al. 2013

The Journal of Immunology

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Tyk2 belongs to the Janus protein tyrosine kinase family and is involved in signaling of immunoregulatory cytokines (type I and III IFNs, IL-6, IL-10, and IL-12 families) via its interaction with shared receptor subunits. Depending on the receptor complex, Tyk2 is coactivated with either Jak1 or Jak2, but a detailed molecular characterization of the interplay between the two enzymes is missing. In human populations, the Tyk2 gene presents high levels of genetic diversity with >100 nonsynonymous variants being detected. In this study, we characterized two rare Tyk2 variants, I684S and P1104A, which have been associated with susceptibility to autoimmune disease. Specifically, we measured their in vitro catalytic activity and their ability to mediate Stat activation in fibroblasts and genotyped B cell lines. Both variants were found to be catalytically impaired but rescued signaling in response to IFN-α/β, IL-6, and IL-10. These data, coupled with functional study of an engineered Jak1 P1084A, support a model of nonhierarchical activation of Janus kinases in which one catalytically competent Jak is sufficient for signaling provided that its partner behaves as proper scaffold, even if inactive. Through the analysis of IFN-α and IFN-γ signaling in cells with different Jak1 P1084A levels, we also illustrate a context in which a hypomorphic Jak can hamper signaling in a cytokine-specific manner. Given the multitude of Tyk2-activating cytokines, the cell context–dependent requirement for Tyk2 and the catalytic defect of the two disease-associated variants studied in this paper, we predict that these alleles are functionally significant in complex immune disorders.

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Section: Discussionmentioning

confidence: 99%

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

Gakovic

Ragimbeau

et al. 2013

The Journal of Immunology

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“…Recent evidence indicates that for receptor-unbound JAK2, the FERM domain may fold back on the JH1 and JH2 domains to provide an additional physical constraint to activation (45). The JAK1 FERM domain is involved in autoinhibition as well (59).…”

Section: Activation Of the Jaksmentioning

confidence: 99%

JAK redux: a second look at the regulation and role of JAKs in the heart

Kurdi

Booz

2009

American Journal of Physiology-Heart and Circulatory Physiology

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number of type 1 receptor cytokine family members protect the heart from acute and chronic oxidative stress. This protection involves activation of two intracellular signaling cascades: the reperfusion injury salvage kinase (RISK) pathway, which entails activation of phosphatidylinositol 3-kinase (PI3-kinase) and ERK1/2, and JAK-STAT signaling, which involves activation of transcription factor signal transducer and activator of transcription 3 (STAT3). Obligatory for activation of both RISK and STAT3 by nearly all of these cytokines are the kinases JAK1 and JAK2. Yet surprisingly little is known about how JAK1 and JAK2 are regulated in the heart or how they couple to PI3-kinase activation. Although the JAKs are linked to antioxidative stress programs in the heart, we recently reported that these kinases are inhibited by oxidative stress in cardiac myocytes. In contrast, others have reported that cardiac JAK2 is activated by acute oxidative stress by an undefined process. Here we summarize recent insights into the regulation of JAK1 and JAK2. Besides oxidative stress, inhibitory regulation involves phosphorylation, nitration, and intramolecular restraints. Stimulatory regulation involves phosphorylation and adaptor proteins. The net effect of stress on JAK activity in the heart likely represents the sum of both inhibitory and stimulatory processes, along with their dynamic interaction. Thus the regulation of JAKs in the heart, once touted as the paragon of simplicity, is proving rather complicated indeed, requiring a second look. It is our contention that a better understanding of the regulation of this kinase family that is implicated in cardiac protection could translate into effective therapeutic strategies for preventing myocardial damage or repairing the injured heart. Janus kinase; oxidative stress; redox; cardiac remodeling; cytokine; cardiac myocyte A NUMBER OF TYPE 1 RECEPTOR cytokine family members, namely the interleukin (IL)-6-type cytokines [IL-6, IL-11, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), and oncostatin M (OSM)] (40, 78, 58, 85), growth hormone (GH; Ref. 91) erythropoietin (Epo; Refs. 20,134,138), and granulocyte colony-stimulating factor (G-CSF; Refs. 26,61,62,72,159,166), as well as insulin (3,23,54,64,99,164,186), have been shown to protect the heart from acute oxidative stress, viz., ischemia-reperfusion injury. LIF (121), GH (56), Epo (77), and insulin (141) have also been reported to protect cardiac myocytes from chronic oxidative stress. Notably, a number of clinical trials have been completed or are underway assessing the efficacy of Epo or G-CSF in treating myocardial infarction and heart failure (13,87,88,93).The protective action of the type 1 receptor cytokines (see Fig. 1 for IL-6 cytokine signaling) and insulin has been shown to involve activation of two intracellular signaling cascades: 1) the reperfusion injury salvage kinase (RISK) pathway (17,27,40,41,64,66,77,99,101,102,108,121,126,128,133,134,142,156,159,160,161,166) and 2) JAK-STAT signaling (20,40,61,85,16...

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“…This possibility leads to the question of what distinguishes IL-27 receptor-␣ from other single chain receptors. It is conceivable that the specific interaction between a receptor scaffold and the FERM domain of a cognate Jak ultimately determines the degree of flexibility of the kinase domains and the degree of substrate accessibility (31,32).…”

Section: Volume 283 • Number 27 • July 4 2008mentioning

confidence: 99%

The Stat3-activating Tyk2 V678F Mutant Does Not Up-regulate Signaling through the Type I Interferon Receptor but Confers Ligand Hypersensitivity to a Homodimeric Receptor

Gakovic

Ragimbeau

François

et al. 2008

Journal of Biological Chemistry

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Tyk2 is a Jak family member involved in cytokine signaling through heterodimeric-type receptors. Here, we analyzed the impact of the Val 678 -to-Phe substitution on Tyk2 functioning. This mutation is homologous to the Jak2 Val 617 -to-Phe mutation, implicated in myeloproliferative disorders. We studied ligand-independent and ligand-dependent Jak/Stat signaling in cells expressing Tyk2 V678F. Moreover, the effect of Tyk2 V678F was monitored in the context of the native heterodimeric interferon ␣ receptor and in the context of a homodimeric receptor chimera, EpoR/R1, containing the ectodomain of the erythropoietin receptor. We show that Tyk2 V678F has increased catalytic potential in vivo and in vitro and more so when it is anchored to the homodimeric receptor. Tyk2 V678F leads to constitutive Stat3 phosphorylation but has no notable effect on the canonical interferon ␣-induced signaling. However, if anchored to the homodimeric EpoR/R1, the mutant confers to the cell increased sensitivity to erythropoietin. Thus, despite the catalytic gain of function of Tyk2 V678F, the effect on ligand-induced signaling is manifest only when two mutant enzymes are juxtaposed via the homodimeric receptor.The protein tyrosine kinases of the Janus or Jak (Janus kinase) family (Tyk2, Jak1-3) initiate signaling cascades through receptors for helix-bundled cytokines. In mammals, these large enzymes are preassociated to the membrane-proximal cytosolic portion of receptors and play non-redundant functions in cytokine-regulated developmental, differentiation, and host defense processes as shown from biochemical analyses and from studies of knock-out mice (1). The present understanding of the molecular mechanism of Jak activation is still fragmentary: some cytokines bind in a two-step process to constitutive receptor homodimers, whereas other cytokines drive dimerization of the distinct subunits of heterodimeric receptors. Conformational and rotational changes are generated and translated across the transmembrane domains so that the juxtaposed Jaks acquire a configuration suitable for transphosphorylation and catalytic activation. This process has been best described for the erythropoietin (Epo) 5 and growth hormone homodimeric receptors, which activate two associated Jak2 molecules (2, 3). Instead, in heteromeric-type receptors the mode of activation of two different Jaks and their specific role remains ill defined.In all Jak proteins, three highly interdependent modules ensure proper regulation of the enzyme. The N-terminal region, comprising a FERM-related domain and a SH2-like domain, makes specific contacts with the cytosolic region of a cognate receptor. The N-terminal region is followed by two kinase folds, the centrally located KL (kinase-like) domain, also called pseudokinase or JH2, and the catalytic TK (tyrosine kinase) or JH1 domain. Upon ligand binding, the degree of activation of these enzymes is commonly monitored by the phosphorylation of critical tyrosines in the activation loop of the TK domain (4). Numerous studies have ...

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Dual Role of the Jak1 FERM and Kinase Domains in Cytokine Receptor Binding and in Stimulation-Dependent Jak Activation

Cited by 52 publications

References 42 publications

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

Two Rare Disease-Associated Tyk2 Variants Are Catalytically Impaired but Signaling Competent

JAK redux: a second look at the regulation and role of JAKs in the heart

The Stat3-activating Tyk2 V678F Mutant Does Not Up-regulate Signaling through the Type I Interferon Receptor but Confers Ligand Hypersensitivity to a Homodimeric Receptor

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