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. 2020 Mar 11.
doi: 10.1002/1873-3468.13769. Online ahead of print.

Nik-related Kinase Is Targeted for Proteasomal Degradation by the Chaperone-Dependent Ubiquitin Ligase CHIP

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Nik-related Kinase Is Targeted for Proteasomal Degradation by the Chaperone-Dependent Ubiquitin Ligase CHIP

Satomi Naito et al. FEBS Lett. .

Abstract

Nik-related kinase (Nrk) is a member of the germinal center kinase IV family and suppresses Akt signaling. In vivo, Nrk prevents placental hyperplasia and breast cancer formation. Here, we show that Nrk is regulated by the chaperone-dependent ubiquitin ligase carboxyl terminus of heat-shock protein (Hsp)70-interacting protein (CHIP). Immunoprecipitation and liquid chromatography-tandem mass spectrometry analysis reveal that Nrk preferentially interacts with CHIP and Hsp70/90 family proteins. Nrk protein levels are decreased by CHIP overexpression and increased by siRNA-mediated CHIP knockdown. Our results indicate that Nrk is ubiquitinated by CHIP in a chaperone-dependent manner, resulting in its proteasomal degradation. CHIP targets a fraction of Nrk molecules that have lost the ability to regulate Akt signaling. We conclude that CHIP plays an important role in regulating Nrk protein levels.

Keywords: CHIP; Nik-related kinase; chaperone; proteostasis; ubiquitin.

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References

    1. Delpire E (2009) The mammalian family of sterile 20p-like protein kinases. Pflugers Arch 458, 953-967.
    1. Xue Y, Wang X, Li Z, Gotoh N, Chapman D and Skolnik EY (2001) Mesodermal patterning defect in mice lacking the Ste20 NCK interacting kinase (NIK). Development 128, 1559-1572.
    1. Coba MP, Komiyama NH, Nithianantharajah J, Kopanitsa MV, Indersmitten T, Skene NG, Tuck EJ, Fricker DG, Elsegood KA, Stanford LE et al. (2012) TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function. J Neurosci 32, 13987-13999.
    1. Masuda M, Uno Y, Ohbayashi N, Ohata H, Mimata A, Kukimoto-Niino M, Moriyama H, Kashimoto S, Inoue T, Goto N et al. (2016) TNIK inhibition abrogates colorectal cancer stemness. Nat Commun 7, 12586.
    1. McCarty N, Paust S, Ikizawa K, Dan I, Li X and Cantor H (2005) Signaling by the kinase MINK is essential in the negative selection of autoreactive thymocytes. Nat Immunol 6, 65-72.

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