Negative regulation of Jak2 by its auto-phosphorylation at tyrosine 913 via the Epo signaling pathway

Megumi Tago, Kenji Tago, Tadashi Kasahara, Evan Parganas, James N. Ihle

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Janus kinase 2 (Jak2) has a pivotal role in erythropoietin (Epo) signaling pathway, including erythrocyte differentiation and Stat5 activation. In the course of screening for critical phosphorylation of tyrosine residues in Jak2, we identified tyrosine 913 (Y913) as a novel and functional phosphorylation site, which negatively regulates Jak2. Phosphorylation at Y913 rapidly occurred and was sustained for at least 120 min after Epo stimulation, in contrast to the transient phosphorylation of Y1007/1008 in the activation loop of Jak2. Interestingly, phosphorylation defective mutation of Y913 (Y913F) results in a significant enhancement of Epo-induced Jak2 activation, whereas phosphorylation mimic mutation of Y913 (Y913E) completely abrogated its activation. Furthermore, Jak2 deficient fetal liver cells expressing Y913F mutant generated many mature erythroid BFU-E and CFU-E colonies, while Y913E mutant failed to reconstitute Jak2 deficiency. We also demonstrate, in Jak1, phosphorylation of Y939, a corresponding tyrosine residue with Y913, negatively regulated Jak1 signaling pathway. Accordingly, our results suggest that this tyrosine phosphorylation in JH1 domain may be involved in common negative regulation mechanism for Jak family.

Original languageEnglish
Pages (from-to)1995-2001
Number of pages7
JournalCellular Signalling
Volume20
Issue number11
DOIs
Publication statusPublished - 2008 Nov

Fingerprint

Janus Kinase 2
Erythropoietin
Tyrosine
Phosphorylation
Erythroid Precursor Cells
Mutation
Erythrocytes

Keywords

  • BFU-E
  • CFU-E
  • Epo
  • Jak2
  • Phosphorylation
  • Y

ASJC Scopus subject areas

  • Cell Biology

Cite this

Negative regulation of Jak2 by its auto-phosphorylation at tyrosine 913 via the Epo signaling pathway. / Tago, Megumi; Tago, Kenji; Kasahara, Tadashi; Parganas, Evan; Ihle, James N.

In: Cellular Signalling, Vol. 20, No. 11, 11.2008, p. 1995-2001.

Research output: Contribution to journalArticle

Tago, Megumi ; Tago, Kenji ; Kasahara, Tadashi ; Parganas, Evan ; Ihle, James N. / Negative regulation of Jak2 by its auto-phosphorylation at tyrosine 913 via the Epo signaling pathway. In: Cellular Signalling. 2008 ; Vol. 20, No. 11. pp. 1995-2001.
@article{82542c003340451fa70baacda0c5de50,
title = "Negative regulation of Jak2 by its auto-phosphorylation at tyrosine 913 via the Epo signaling pathway",
abstract = "Janus kinase 2 (Jak2) has a pivotal role in erythropoietin (Epo) signaling pathway, including erythrocyte differentiation and Stat5 activation. In the course of screening for critical phosphorylation of tyrosine residues in Jak2, we identified tyrosine 913 (Y913) as a novel and functional phosphorylation site, which negatively regulates Jak2. Phosphorylation at Y913 rapidly occurred and was sustained for at least 120 min after Epo stimulation, in contrast to the transient phosphorylation of Y1007/1008 in the activation loop of Jak2. Interestingly, phosphorylation defective mutation of Y913 (Y913F) results in a significant enhancement of Epo-induced Jak2 activation, whereas phosphorylation mimic mutation of Y913 (Y913E) completely abrogated its activation. Furthermore, Jak2 deficient fetal liver cells expressing Y913F mutant generated many mature erythroid BFU-E and CFU-E colonies, while Y913E mutant failed to reconstitute Jak2 deficiency. We also demonstrate, in Jak1, phosphorylation of Y939, a corresponding tyrosine residue with Y913, negatively regulated Jak1 signaling pathway. Accordingly, our results suggest that this tyrosine phosphorylation in JH1 domain may be involved in common negative regulation mechanism for Jak family.",
keywords = "BFU-E, CFU-E, Epo, Jak2, Phosphorylation, Y",
author = "Megumi Tago and Kenji Tago and Tadashi Kasahara and Evan Parganas and Ihle, {James N.}",
year = "2008",
month = "11",
doi = "10.1016/j.cellsig.2008.07.008",
language = "English",
volume = "20",
pages = "1995--2001",
journal = "Cellular Signalling",
issn = "0898-6568",
publisher = "Elsevier Inc.",
number = "11",

}

TY - JOUR

T1 - Negative regulation of Jak2 by its auto-phosphorylation at tyrosine 913 via the Epo signaling pathway

AU - Tago, Megumi

AU - Tago, Kenji

AU - Kasahara, Tadashi

AU - Parganas, Evan

AU - Ihle, James N.

PY - 2008/11

Y1 - 2008/11

N2 - Janus kinase 2 (Jak2) has a pivotal role in erythropoietin (Epo) signaling pathway, including erythrocyte differentiation and Stat5 activation. In the course of screening for critical phosphorylation of tyrosine residues in Jak2, we identified tyrosine 913 (Y913) as a novel and functional phosphorylation site, which negatively regulates Jak2. Phosphorylation at Y913 rapidly occurred and was sustained for at least 120 min after Epo stimulation, in contrast to the transient phosphorylation of Y1007/1008 in the activation loop of Jak2. Interestingly, phosphorylation defective mutation of Y913 (Y913F) results in a significant enhancement of Epo-induced Jak2 activation, whereas phosphorylation mimic mutation of Y913 (Y913E) completely abrogated its activation. Furthermore, Jak2 deficient fetal liver cells expressing Y913F mutant generated many mature erythroid BFU-E and CFU-E colonies, while Y913E mutant failed to reconstitute Jak2 deficiency. We also demonstrate, in Jak1, phosphorylation of Y939, a corresponding tyrosine residue with Y913, negatively regulated Jak1 signaling pathway. Accordingly, our results suggest that this tyrosine phosphorylation in JH1 domain may be involved in common negative regulation mechanism for Jak family.

AB - Janus kinase 2 (Jak2) has a pivotal role in erythropoietin (Epo) signaling pathway, including erythrocyte differentiation and Stat5 activation. In the course of screening for critical phosphorylation of tyrosine residues in Jak2, we identified tyrosine 913 (Y913) as a novel and functional phosphorylation site, which negatively regulates Jak2. Phosphorylation at Y913 rapidly occurred and was sustained for at least 120 min after Epo stimulation, in contrast to the transient phosphorylation of Y1007/1008 in the activation loop of Jak2. Interestingly, phosphorylation defective mutation of Y913 (Y913F) results in a significant enhancement of Epo-induced Jak2 activation, whereas phosphorylation mimic mutation of Y913 (Y913E) completely abrogated its activation. Furthermore, Jak2 deficient fetal liver cells expressing Y913F mutant generated many mature erythroid BFU-E and CFU-E colonies, while Y913E mutant failed to reconstitute Jak2 deficiency. We also demonstrate, in Jak1, phosphorylation of Y939, a corresponding tyrosine residue with Y913, negatively regulated Jak1 signaling pathway. Accordingly, our results suggest that this tyrosine phosphorylation in JH1 domain may be involved in common negative regulation mechanism for Jak family.

KW - BFU-E

KW - CFU-E

KW - Epo

KW - Jak2

KW - Phosphorylation

KW - Y

UR - http://www.scopus.com/inward/record.url?scp=52149086993&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=52149086993&partnerID=8YFLogxK

U2 - 10.1016/j.cellsig.2008.07.008

DO - 10.1016/j.cellsig.2008.07.008

M3 - Article

VL - 20

SP - 1995

EP - 2001

JO - Cellular Signalling

JF - Cellular Signalling

SN - 0898-6568

IS - 11

ER -