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Mol Cell Biol. 2015 Jan;35(1):111-31. doi: 10.1128/MCB.01138-14. Epub 2014 Oct 20.

JAK2 tyrosine kinase phosphorylates and is negatively regulated by centrosomal protein Ninein.

Author information

1
Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA.
2
Advanced Microscopy & Imaging Center, University of Toledo, Toledo, Ohio, USA.
3
Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA mdiakon@utnet.utoledo.edu.

Abstract

JAK2 is a cytoplasmic tyrosine kinase critical for cytokine signaling. In this study, we have identified a novel centrosome-associated complex containing ninein and JAK2. We have found that active JAK2 localizes around the mother centrioles, where it partly colocalizes with ninein, a protein involved in microtubule (MT) nucleation and anchoring. We demonstrated that JAK2 is an important regulator of centrosome function. Depletion of JAK2 or use of JAK2-null cells causes defects in MT anchoring and increased numbers of cells with mitotic defects; however, MT nucleation is unaffected. We showed that JAK2 directly phosphorylates the N terminus of ninein while the C terminus of ninein inhibits JAK2 kinase activity in vitro. Overexpressed wild-type (WT) or C-terminal (amino acids 1179 to 1931) ninein inhibits JAK2. This ninein-dependent inhibition of JAK2 significantly decreases prolactin- and interferon gamma (IFN-γ)-induced tyrosyl phosphorylation of STAT1 and STAT5. Downregulation of ninein enhances JAK2 activation. These results indicate that JAK2 is a novel member of centrosome-associated complex and that this localization regulates both centrosomal function and JAK2 kinase activity, thus controlling cytokine-activated molecular pathways.

PMID:
25332239
PMCID:
PMC4295371
DOI:
10.1128/MCB.01138-14
[Indexed for MEDLINE]
Free PMC Article

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