title: Jak2 FERM domain interaction with the erythropoietin receptor regulates Jak2 kinase activity.
abstract: Janus kinases are essential for signal transduction by a variety of cytokine receptors and when inappropriately activated can cause hematopoietic disorders and oncogenesis. Consequently, it can be predicted that the interaction of the kinases with receptors and the events required for activation are highly controlled. In a screen to identify phosphorylation events regulating Jak2 activity in EpoR signaling, we identified a mutant (Jak2-Y613E) which has the property of being constitutively activated, as well as an inactivating mutation (Y766E). Although no evidence was obtained to indicate that either site is phosphorylated in signaling, the consequences of the Y613E mutation are similar to those observed with recently described activating mutations in Jak2 (Jak2-V617F and Jak2-L611S). However, unlike the V617F or L611S mutant, the Y613E mutant requires the presence of the receptor but not Epo stimulation for activation and downstream signaling. The properties of the Jak2-Y613E mutant suggest that under normal conditions, Jak2 that is not associated with a receptor is locked into an inactive state and receptor binding through the FERM domain relieves steric constraints, allowing the potential to be activated with receptor engagement.
authors.affiliation: Department of Biochemistry, D4013, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, Tennessee 38105, USA.
authors.forename: Megumi
authors.initials: M
authors.lastname: Funakoshi-Tago
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pelletier
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Moritake
authors.forename: Evan
authors.initials: E
authors.lastname: Parganas
authors.forename: James N
authors.initials: JN
authors.lastname: Ihle
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D018076:DNA, Complementary; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D008954:Models, Biological; D010649:Phenylalanine / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D017467:Receptors, Erythropoietin; D010649:Phenylalanine; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2