title: Phosphorylation of p27Kip1 by JAK2 directly links cytokine receptor signaling to cell cycle control.
abstract: Janus kinase 2 (JAK2) couples ligand activation of cell surface cytokine receptors to the regulation of cellular functions including cell cycle progression, differentiation and apoptosis. It thereby coordinates biological programs such as development and hematopoiesis. Unscheduled activation of JAK2 by point mutations or chromosomal translocations can induce hyperproliferation and hematological malignancies. Typical signal transduction by the JAK2 tyrosine kinase comprises phosphorylation of STAT transcription factors. In this study, we describe the identification of the cyclin-dependent kinase (CDK) inhibitor p27(Kip1) as a novel JAK2 substrate. JAK2 can directly bind and phosphorylate p27(Kip1). Both, the JAK2 FERM domain and its kinase domain bind to p27(Kip1). JAK2 phosphorylates tyrosine residue 88 (Y88) of p27(Kip1). We previously reported that Y88 phosphorylation of p27(Kip1) by oncogenic tyrosine kinases impairs p27(Kip1)-mediated CDK inhibition, and initiates its ubiquitin-dependent proteasomal degradation. Consistently, we now find that active oncogenic JAK2V617F reduces p27(Kip1) stability and protein levels in patient-derived cell lines harboring the mutant JAK2V617F allele. Moreover, tyrosine phosphorylation of p27(Kip1) is impaired and p27(Kip1) expression is restored upon JAK2V617F inactivation by small hairpin RNA-mediated knockdown or by the pyridone-containing tetracycle JAK inhibitor-I, indicating that direct phosphorylation of p27(Kip1) can contribute to hyperproliferation of JAK2V617F-transformed cells. Activation of endogenous JAK2 by interleukin-3 (IL-3) induces Y88 phosphorylation of p27(Kip1), thus unveiling a novel link between cytokine signaling and cell cycle control in non-transformed cells. Oncogenic tyrosine kinases could use this novel pathway to promote hyperproliferation in tumor cells.
authors.affiliation: Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Jäkel
authors.forename: C
authors.initials: C
authors.lastname: Weinl
authors.forename: L
authors.initials: L
authors.lastname: Hengst
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007377:Interleukin-3 / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D034622:RNA Interference; D018121:Receptors, Cytokine / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013379:Substrate Specificity; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: D007377:Interleukin-3; D018121:Receptors, Cytokine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014443:Tyrosine; D053614:Janus Kinase 2