Regulation of p27 (Kip1) by mitogen-induced tyrosine phosphorylation.

Cell Cycle
Heidelinde JäkelLudger Hengst

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.

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Citations

Mar 22, 2014·PloS One·Glen A BjerkeDavid Wotton
Oct 30, 2015·Proceedings of the National Academy of Sciences of the United States of America·Linda FabrisGustavo Baldassarre
Aug 19, 2015·The International Journal of Biochemistry & Cell Biology·Su Su Thae HnitQihan Dong
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Apr 18, 2019·Scientific Reports·Arthur W CurrierValerie B Sampson
Apr 18, 2018·Oncotarget·Edurne GallasteguiOriol Bachs

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