Structural modeling of JAK1 mutations in T-cell acute lymphoblastic leukemia reveals a second contact site between pseudokinase and kinase domains

Canté-Barrett, Kirsten; Uitdehaag, Joost C.M.; Meijerink, Jules P.P.

doi:10.3324/haematol.2015.138248

Cited by 9 publications

(8 citation statements)

References 19 publications

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“…It resides in the N-lobe of JH2 (similarly to homologous JAK2 R683S) and interacts with JH1. Other JAK1 mutants in the JH1-JH2 interface are A634D and L653F [21,22].…”

Section: Introductionmentioning

confidence: 99%

Characterization of JAK1 Pseudokinase Domain in Cytokine Signaling

Raivola

Haikarainen

Silvennoinen

2019

Cancers

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The Janus kinase-signal transducer and activator of transcription protein (JAK-STAT) pathway mediates essential biological functions from immune responses to haematopoiesis. Deregulated JAK-STAT signaling causes myeloproliferative neoplasms, leukaemia, and lymphomas, as well as autoimmune diseases. Thereby JAKs have gained significant relevance as therapeutic targets. However, there is still a clinical need for better JAK inhibitors and novel strategies targeting regions outside the conserved kinase domain have gained interest. In-depth knowledge about the molecular details of JAK activation is required. For example, whether the function and regulation between receptors is conserved remains an open question. We used JAK-deficient cell-lines and structure-based mutagenesis to study the function of JAK1 and its pseudokinase domain (JH2) in cytokine signaling pathways that employ JAK1 with different JAK heterodimerization partner. In interleukin-2 (IL-2)-induced STAT5 activation JAK1 was dominant over JAK3 but in interferon-γ (IFNγ) and interferon-α (IFNα) signaling both JAK1 and heteromeric partner JAK2 or TYK2 were both indispensable for STAT1 activation. Moreover, IL-2 signaling was strictly dependent on both JAK1 JH1 and JH2 but in IFNγ signaling JAK1 JH2 rather than kinase activity was required for STAT1 activation. To investigate the regulatory function, we focused on two allosteric regions in JAK1 JH2, the ATP-binding pocket and the αC-helix. Mutating L633 at the αC reduced basal and cytokine induced activation of STAT in both JAK1 wild-type (WT) and constitutively activated mutant backgrounds. Moreover, biochemical characterization and comparison of JH2s let us depict differences in the JH2 ATP-binding and strengthen the hypothesis that de-stabilization of the domain disturbs the regulatory JH1-JH2 interaction. Collectively, our results bring mechanistic understanding about the function of JAK1 in different receptor complexes that likely have relevance for the design of specific JAK modulators.

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“…It resides in the N-lobe of JH2 (similarly to homologous JAK2 R683S) and interacts with JH1. Other JAK1 mutants in the JH1-JH2 interface are A634D and L653F [21,22].…”

Section: Introductionmentioning

confidence: 99%

Characterization of JAK1 Pseudokinase Domain in Cytokine Signaling

Raivola

Haikarainen

Silvennoinen

2019

Cancers

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“…In this state, K622 forms two H-bonds with S738 ( Figure 6 e). Within this structural confirmation, V666 is located near hypothetical salt bridges, proposed by Cante-Barrett et al in the pseudokinase hinge (residues 666–736) that interacts with the JH1 kinase domain loop (residues 893–904) [ 42 ]. The indirect relationship between V666 and R879, seen in Figure 6 d, may be critical for stabilizing the pseudokinase–kinase interface.…”

Section: Resultsmentioning

confidence: 81%

JAK1 Pseudokinase V666G Mutant Dominantly Impairs JAK3 Phosphorylation and IL-2 Signaling

Grant

Rodrı́guez

Moncivais

et al. 2023

IJMS

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Overactive Janus kinases (JAKs) are known to drive leukemia, making them well-suited targets for treatment. We sought to identify new JAK-activating mutations and instead found a JAK1-inactivating pseudokinase mutation, V666G. In contrast to other pseudokinase mutations that canonically lead to an active kinase, the JAK1 V666G mutation led to under-activation seen by reduced phosphorylation. To understand the functional role of JAK1 V666G in modifying kinase activity we investigated its influence on other JAK kinases and within the Interleukin-2 pathway. JAK1 V666G not only inhibited its own activity, but its presence could inhibit other JAK kinases. These findings provide new insights into the potential of JAK1 pseudokinase to modulate its own activity, as well as of other JAK kinases. Thus, the features of the JAK1 V666 region in modifying JAK kinases can be exploited to allosterically inhibit overactive JAKs.

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“…TYK2 is associated with the receptors of type I IFN (IFNα/β), interleukin (IL)-6, IL-10, IL-11, IL-12, IL-23, and IL-27. Disease-driving mutations in TYK2 are rarely found in leukemia when compared to other JAK family members [ 87 ]. No somatic TYK2 mutations were found in a study with 186 acute adulthood leukemia samples [ 60 ] or 424 sporadic ALL cases [ 88 ], suggesting that the hematopoietic lineages are more affected by mutations in JAK1, JAK2, and JAK3.…”

Section: Jaks In Leukemiamentioning

confidence: 99%

“…In addition to FERM domain, JH1 harbors several activating mutations. Majority of these mutations seem to have a similar activation mechanism as non-dimerizing JH2 mutations, i.e., they are located at the inhibitory JH2-JH1 interface and the mutations presumably lead to the disruption of the autoinhibitory interface [ 33 , 34 , 87 ].…”

Section: Jaks In Leukemiamentioning

confidence: 99%

Janus Kinases in Leukemia

Raivola

Haikarainen

Abraham

et al. 2021

Cancers

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Janus kinases (JAKs) transduce signals from dozens of extracellular cytokines and function as critical regulators of cell growth, differentiation, gene expression, and immune responses. Deregulation of JAK/STAT signaling is a central component in several human diseases including various types of leukemia and other malignancies and autoimmune diseases. Different types of leukemia harbor genomic aberrations in all four JAKs (JAK1, JAK2, JAK3, and TYK2), most of which are activating somatic mutations and less frequently translocations resulting in constitutively active JAK fusion proteins. JAKs have become important therapeutic targets and currently, six JAK inhibitors have been approved by the FDA for the treatment of both autoimmune diseases and hematological malignancies. However, the efficacy of the current drugs is not optimal and the full potential of JAK modulators in leukemia is yet to be harnessed. This review discusses the deregulation of JAK-STAT signaling that underlie the pathogenesis of leukemia, i.e., mutations and other mechanisms causing hyperactive cytokine signaling, as well as JAK inhibitors used in clinic and under clinical development.

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Structural modeling of JAK1 mutations in T-cell acute lymphoblastic leukemia reveals a second contact site between pseudokinase and kinase domains

Cited by 9 publications

References 19 publications

Characterization of JAK1 Pseudokinase Domain in Cytokine Signaling

Characterization of JAK1 Pseudokinase Domain in Cytokine Signaling

JAK1 Pseudokinase V666G Mutant Dominantly Impairs JAK3 Phosphorylation and IL-2 Signaling

Janus Kinases in Leukemia

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