Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation-loop mutation
| Autor: | Mathias Müller, Pia Liebfried, David Finkenstädt, Christian Wufka, Birgit Strobl, Eric Keil, Mirko Trilling, Klaus Pfeffer |
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| Rok vydání: | 2013 |
| Předmět: |
Immunology
Medizin Mice Transgenic medicine.disease_cause Biochemistry Mice hemic and lymphatic diseases medicine Receptors Erythropoietin Homomeric Animals Phosphorylation Alleles Cells Cultured Receptors Interferon Mutation Janus kinase 2 biology food and beverages Gene targeting Cell Biology Hematology Janus Kinase 1 Fibroblasts Janus Kinase 2 Null allele Erythropoietin receptor Phenotype biology.protein Cancer research Tyrosine Signal transduction Janus kinase hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Blood. 123(4) |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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