title: Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation-loop mutation.
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 Jak2(FF/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 semi-redundant 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.
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany;
authors.forename: Eric
authors.initials: E
authors.lastname: Keil
authors.forename: David
authors.initials: D
authors.lastname: Finkenstädt
authors.forename: Christian
authors.initials: C
authors.lastname: Wufka
authors.forename: Mirko
authors.initials: M
authors.lastname: Trilling
authors.forename: Pia
authors.initials: P
authors.lastname: Liebfried
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
mesh_terms: D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D017467:Receptors, Erythropoietin / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D053613:Janus Kinase 1; D053614:Janus Kinase 2; D017467:Receptors, Erythropoietin; D017471:Receptors, Interferon; D014443:Tyrosine; D000096743:Interferon gamma Receptor; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse