title: Regulation of p27 (Kip1)  by mitogen-induced tyrosine phosphorylation.
abstract: Extracellular mitogen signal transduction is initiated by ligand binding to specific receptors of target cells. This causes a cellular response that frequently triggers the activation of tyrosine kinases. Non-receptor kinases like Src and Lyn can directly phosphorylate the Cdk inhibitor protein p27 (Kip1) . Tyrosine phosphorylation can cause impaired Cdk-inhibitory activity and decreased stability of p27. In addition to these non-receptor tyrosine kinases, the receptor-associated tyrosine kinase Janus kinase 2 (JAK2) was recently identified to phosphorylate p27. JAK2 becomes activated through binding of various cytokines and growth factors to their corresponding receptors and can directly bind and selectively phosphorylate tyrosine residue 88 (Y88) of the Cdk inhibitor p27. This impairs Cdk inhibition by p27 and promotes its ubiquitin-dependent proteasomal degradation. Via this mechanism, JAK2 can link cytokine and growth factor initiated signal transduction to p27 regulation, whereas oncogenes like JAK2V617F or BCR-Abl can use this mechanism to inactivate the Cdk inhibitor.
authors.affiliation: Division of Medical Biochemistry; Biocenter; Innsbruck Medical University; Innsbruck, Austria.
authors.forename: Heidelinde
authors.initials: H
authors.lastname: Jäkel
authors.forename: Ines
authors.initials: I
authors.lastname: Peschel
authors.forename: Clarissa
authors.initials: C
authors.lastname: Kunze
authors.forename: Christina
authors.initials: C
authors.lastname: Weinl
authors.forename: Ludger
authors.initials: L
authors.lastname: Hengst
mesh_terms: D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007399:Interphase; D053614:Janus Kinase 2 / Q000378:metabolism; D008934:Mitogens / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
chemical_list: D008934:Mitogens; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014443:Tyrosine; D053614:Janus Kinase 2; D046988:Proteasome Endopeptidase Complex