Distinct Domains of the Protein Tyrosine Kinase tyk2 Required for Binding of Interferon-α/β and for Signal Transduction

Velázquez, Laura Evelia Torres; Mogensen, K. E.; Barbieri, Giovanna; Fellous, Marc; Uzé, Gilles; Pellegrini, Sandra

doi:10.1074/jbc.270.7.3327

Cited by 143 publications

(138 citation statements)

References 40 publications

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“…Therefore, it is critical to define the domains in Jaks and cytokine receptors responsible for this interaction to mimic or abrogate the activation of cytokine systems with specific drugs. Some reports have indicated that the N-terminal region, containing the JH7-6 domains, of Jak2, Jak3, and Tyk2 is critical for the association with receptors (42)(43)(44)(45)(46)(47)(48)(49). Our data (Fig.…”

Section: Discussionsupporting

confidence: 58%

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Two Distinct Domains Within the N-Terminal Region of Janus Kinase 1 Interact with Cytokine Receptors

Usacheva

Witte

Colamonici

2002

The Journal of Immunology

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The interaction between receptors and kinases of the Janus kinase (Jak) family is critical for signaling by growth factors, cytokines, and IFNs. Therefore, the characterization of the domains involved in these interactions is pivotal not only in understanding kinase activation but also in the development of drugs that mimic or inhibit signaling. In this report, we have characterized the domains of Jak1 required to associate with distinct cytokine receptor subunits: IFN-αRβL, IFN-γRα, IL-10Rα, IL-2Rβ, and IL-4Rα. We demonstrate that two regions of Jak1 are necessary for the interaction with cytokine receptors. First, a common N-terminal region that includes Jak homology (JH) domain 7 and the first 19 aa of JH6, and, second, a C-terminal region (JH6–3) that was different for distinct receptors. The contribution of the two different regions of Jak1 to cytokine receptor binding was also variable. Deletion of JH7–6 impaired the association of IL-2Rβ and IL-4Rα chains with Jak1 but did not have a major impact on the binding of Jak1 to IFN-αRβL or IL-10Rα. Interestingly, regardless of the effect on receptor binding, removal of JH7–6 completely abrogated kinase activation, indicating that this domain is required for ligand-driven kinase activation and, thus, for proper signaling through cytokine receptors.

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Section: Discussionsupporting

confidence: 58%

“…The JH7-6 domains of Tyk2 interact with IFN-␣R. Although a direct interaction between the JH5-4-3 domains of Tyk2 and IFN-␣R␣ has not been established, these domains are also required for kinase activation by the receptor (47)(48)(49).…”

mentioning

confidence: 99%

Two Distinct Domains Within the N-Terminal Region of Janus Kinase 1 Interact with Cytokine Receptors

Usacheva

Witte

Colamonici

2002

The Journal of Immunology

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“…This interaction does not require Tyk-2 kinase activity, but may require the presence of the kinase domain of Tyk-2 since the Tyk-2KD-mutant failed to associate with Jak-l. Second, the Tyk-2 kinase is constitutively present as a homodimer with the ability of intermolecular tyrosine phosphorylation. The interaction between the Tyk-2 and Jak-1 kinases plays a role in the assembly of the high affinity IFNc~R explaining the finding that mutant cells that lack either Tyk-2 or Jak-1 bind IFNct with low affinity [9,23]. Altogether these data lead us to propose a model in which activation of the IFNct system can be separated in different stages (Fig.…”

Section: Intermolecular Tyrosine Phosphorylation Of the Tyk-2 Dimersmentioning

confidence: 93%

“…et al [23] have demonstrated that mutant U1D cells bind IFNc~ with low affinity, and that transfection of Tyk-2 restores high affinity binding. The low affinity binding observed in U 1D cells [23] resembles the low affinity receptors observed in mouse transfectants that only express the human fl subunit of the type I IFN-R [7]. These findings led us to hypothesize that an interaction, either direct or through adapter proteins, between the Tyk-2 and Jak-1 kinases brings together the ~ and fl subunits to form the high affinity receptor.…”

Section: Introductionmentioning

confidence: 99%

Homodimerization and intermolecular tyrosine phosphorylation of the Tyk‐2 tyrosine kinase

1995

FEBS Letters

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The Jak kinases and Stat transcription factors play a major role in signaling of various cytokines including IFNa. In this report we show a ligand-independent interaction between Tyk-2 and Jak-I kinases. We also demonstrate that the Tyk-2 kinase forms a homodimer that has the ability to undergo intermolecular tyrosine phosphorylation. The formation of the Tyk-2 homodimer is independent of both tyrosine phosphorylation and the presence of the tyrosine kinase domain.

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“…A unique feature of the Jak family is the existence of an additional domain called pseudokinase(JH2) domain. As the kinase domain (JH1) has all of the features of a typical tyrosine kinase domain, the function of the pseudokinase domain is unclear, while pseudokinase domain may have lost the catalytic activity, as lacking of some key residues (Velazquez et al 1995;Luo et al 1997). Some experimental evidence has shown abnormal phenotypes when some residues are mutated in the pseudokinase domain or the whole region is deleted in the knock-out mice (Guschin et al 1995;Feng et al 1997;Zhou et al 1997).…”

Section: Prediction Of Critical Amino Acids Responsible For Functionamentioning

confidence: 99%

Functional divergence and age distribution of vertebrate gene families

Wang

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This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer.The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction.In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion.Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps.Photographs included in the original manuscript have been reproduced xerographically in this copy.Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. Functional Divergence after Gene (Domain) DuplicationGene duplication has long been thought to be a primary source of material for the origin of functional novelties Sidow 1996). Similarly, domain shuffling (or domain duplication) is proposed to be a major evolutionary force to generate multidomain proteins (Henikoff et al. 1997). In theory, gene duplication or/and domain shuffling events resulted in gene families and supergene families, in which several paralogous genes with sequence similarity employ related but distinct functions (Lundin 1993; Hughes 1994; Spring 1996). Under a conventional model, after gene (domain) Irving et al, 2001). However, since they are usually based on some empirical rules rather than a statistical model, the reliability of predictions needs to be justified or at least just made explicit. Structural Basis of Functional Divergence after Gene (Domain) DuplicationIn the post-genomic era, one can expect more and more 3D structures of proteins will be determined due to high throughput structure determination approaches. In many cases, two homologous proteins with related but distinct functions have very similar 3D structures. On the other hand, several studies have shown that some residue changes that have dramatic consequences in physiology are not structurally important sites. It is interesting to investigate the interrelationship between functional divergence, protein structure and molecular evolution. Indeed, many amino acid changes caused by stochastic process are not related to functional divergence and thus do not result in structure changes. analysis provides a useful tool to build up a genome-level hierarchy of gene families.One of the objectives of this study is to explore the evolutionary patterns in more than 2000 vertebrate gene families and to shed a light on the mecha...

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Distinct Domains of the Protein Tyrosine Kinase tyk2 Required for Binding of Interferon-α/β and for Signal Transduction

Cited by 143 publications

References 40 publications

Two Distinct Domains Within the N-Terminal Region of Janus Kinase 1 Interact with Cytokine Receptors

Two Distinct Domains Within the N-Terminal Region of Janus Kinase 1 Interact with Cytokine Receptors

Homodimerization and intermolecular tyrosine phosphorylation of the Tyk‐2 tyrosine kinase

Functional divergence and age distribution of vertebrate gene families

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