The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling

Daniela Ungureanu, Jinhua Wu, Tuija Pekkala, Yashavanthi Niranjan, Clifford Young, Ole N Jensen, Chong-Feng Xu, Thomas A Neubert, Radek C Skoda, Stevan R Hubbard, Olli Silvennoinen

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Resumé

Human JAK2 tyrosine kinase mediates signaling through numerous cytokine receptors. The JAK2 JH2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of JAK2 remains unknown. Mutations in JH2 lead to increased JAK2 activity, contributing to myeloproliferative neoplasms (MPNs). Here we show that JH2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in JAK2: Ser523 and Tyr570. Inactivation of JH2 catalytic activity increased JAK2 basal activity and downstream signaling. Notably, different MPN mutations abrogated JH2 activity in cells, and in MPN (V617F) patient cells phosphorylation of Tyr570 was reduced, suggesting that loss of JH2 activity contributes to the pathogenesis of MPNs. These results identify the catalytic activity of JH2 as a previously unrecognized mechanism to control basal activity and signaling of JAK2.
OriginalsprogEngelsk
TidsskriftNature Structural and Molecular Biology
Vol/bind18
Udgave nummer9
Sider (fra-til)971-976
ISSN1545-9993
DOI
StatusUdgivet - 14. aug. 2011

Fingeraftryk

Neoplasms
Mutation
Cytokine Receptors

Citer dette

Ungureanu, Daniela ; Wu, Jinhua ; Pekkala, Tuija ; Niranjan, Yashavanthi ; Young, Clifford ; Jensen, Ole N ; Xu, Chong-Feng ; Neubert, Thomas A ; Skoda, Radek C ; Hubbard, Stevan R ; Silvennoinen, Olli. / The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. I: Nature Structural and Molecular Biology. 2011 ; Bind 18, Nr. 9. s. 971-976.
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title = "The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling",
abstract = "Human JAK2 tyrosine kinase mediates signaling through numerous cytokine receptors. The JAK2 JH2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of JAK2 remains unknown. Mutations in JH2 lead to increased JAK2 activity, contributing to myeloproliferative neoplasms (MPNs). Here we show that JH2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in JAK2: Ser523 and Tyr570. Inactivation of JH2 catalytic activity increased JAK2 basal activity and downstream signaling. Notably, different MPN mutations abrogated JH2 activity in cells, and in MPN (V617F) patient cells phosphorylation of Tyr570 was reduced, suggesting that loss of JH2 activity contributes to the pathogenesis of MPNs. These results identify the catalytic activity of JH2 as a previously unrecognized mechanism to control basal activity and signaling of JAK2.",
author = "Daniela Ungureanu and Jinhua Wu and Tuija Pekkala and Yashavanthi Niranjan and Clifford Young and Jensen, {Ole N} and Chong-Feng Xu and Neubert, {Thomas A} and Skoda, {Radek C} and Hubbard, {Stevan R} and Olli Silvennoinen",
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Ungureanu, D, Wu, J, Pekkala, T, Niranjan, Y, Young, C, Jensen, ON, Xu, C-F, Neubert, TA, Skoda, RC, Hubbard, SR & Silvennoinen, O 2011, 'The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling', Nature Structural and Molecular Biology, bind 18, nr. 9, s. 971-976. https://doi.org/10.1038/nsmb.2099

The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. / Ungureanu, Daniela; Wu, Jinhua; Pekkala, Tuija; Niranjan, Yashavanthi; Young, Clifford; Jensen, Ole N; Xu, Chong-Feng; Neubert, Thomas A; Skoda, Radek C; Hubbard, Stevan R; Silvennoinen, Olli.

I: Nature Structural and Molecular Biology, Bind 18, Nr. 9, 14.08.2011, s. 971-976.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling

AU - Ungureanu, Daniela

AU - Wu, Jinhua

AU - Pekkala, Tuija

AU - Niranjan, Yashavanthi

AU - Young, Clifford

AU - Jensen, Ole N

AU - Xu, Chong-Feng

AU - Neubert, Thomas A

AU - Skoda, Radek C

AU - Hubbard, Stevan R

AU - Silvennoinen, Olli

PY - 2011/8/14

Y1 - 2011/8/14

N2 - Human JAK2 tyrosine kinase mediates signaling through numerous cytokine receptors. The JAK2 JH2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of JAK2 remains unknown. Mutations in JH2 lead to increased JAK2 activity, contributing to myeloproliferative neoplasms (MPNs). Here we show that JH2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in JAK2: Ser523 and Tyr570. Inactivation of JH2 catalytic activity increased JAK2 basal activity and downstream signaling. Notably, different MPN mutations abrogated JH2 activity in cells, and in MPN (V617F) patient cells phosphorylation of Tyr570 was reduced, suggesting that loss of JH2 activity contributes to the pathogenesis of MPNs. These results identify the catalytic activity of JH2 as a previously unrecognized mechanism to control basal activity and signaling of JAK2.

AB - Human JAK2 tyrosine kinase mediates signaling through numerous cytokine receptors. The JAK2 JH2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of JAK2 remains unknown. Mutations in JH2 lead to increased JAK2 activity, contributing to myeloproliferative neoplasms (MPNs). Here we show that JH2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in JAK2: Ser523 and Tyr570. Inactivation of JH2 catalytic activity increased JAK2 basal activity and downstream signaling. Notably, different MPN mutations abrogated JH2 activity in cells, and in MPN (V617F) patient cells phosphorylation of Tyr570 was reduced, suggesting that loss of JH2 activity contributes to the pathogenesis of MPNs. These results identify the catalytic activity of JH2 as a previously unrecognized mechanism to control basal activity and signaling of JAK2.

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DO - 10.1038/nsmb.2099

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JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

SN - 1545-9993

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