Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation-loop mutation
E Keil, D Finkenstädt, C Wufka, M Trilling… - Blood, The Journal …, 2014 - ashpublications.org
E Keil, D Finkenstädt, C Wufka, M Trilling, P Liebfried, B Strobl, M Müller, K Pfeffer
Blood, The Journal of the American Society of Hematology, 2014•ashpublications.orgJanus kinases (Jak) play essential roles in cytokine and growth factor signaling.
Conventional gene targeting of Jak2, creating a null allele, leads to a block in definitive
erythropoiesis as a result of failing signal transduction at the homomeric erythropoietin
receptor (EpoR) and at the heteromeric interferon γ receptor (IFNGR). To investigate the in
vivo relevance of the activation loop of Jak2, a Jak2-YY1007/1008FF knockin mutation was
introduced into the germline of mice. The phenotype of the Jak2FF/FF mouse line reveals …
Conventional gene targeting of Jak2, creating a null allele, leads to a block in definitive
erythropoiesis as a result of failing signal transduction at the homomeric erythropoietin
receptor (EpoR) and at the heteromeric interferon γ receptor (IFNGR). To investigate the in
vivo relevance of the activation loop of Jak2, a Jak2-YY1007/1008FF knockin mutation was
introduced into the germline of mice. The phenotype of the Jak2FF/FF mouse line reveals …
Abstract
Janus kinases (Jak) play essential roles in cytokine and growth factor signaling. Conventional gene targeting of Jak2, creating a null allele, leads to a block in definitive erythropoiesis as a result of failing signal transduction at the homomeric erythropoietin receptor (EpoR) and at the heteromeric interferon γ receptor (IFNGR). To investigate the in vivo relevance of the activation loop of Jak2, a Jak2-YY1007/1008FF knockin mutation was introduced into the germline of mice. The phenotype of the Jak2FF/FF mouse line reveals that tyrosine residues 1007/1008 are absolutely essential for kinase function and signal transduction at the homomeric EpoR. Detailed studies using the Jak2 activation loop mutant uncover an essential scaffolding function of Jak2 within the IFNGR receptor complex and reveal that Jak1 can mediate a semiredundant function for IFNGR signal transduction. These studies are highly important for the molecular understanding of cytokine and growth factor signaling and provide new insights for future strategies in the design of pharmacological blockers of Jak2.
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