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Sasaki, Mari
Publications (2 of 2) Show all publications
Sasaki, M., Terabayashi, T., Weiss, S. M. & Ferby, I. (2018). The Tumor Suppressor MIG6 Controls Mitotic Progression and the G2/M DNA Damage Checkpoint by Stabilizing the WEE1 Kinase. Cell reports, 24(5), 1278-1289, Article ID S2211-1247(18)30991-4.
Open this publication in new window or tab >>The Tumor Suppressor MIG6 Controls Mitotic Progression and the G2/M DNA Damage Checkpoint by Stabilizing the WEE1 Kinase
2018 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 24, no 5, p. 1278-1289, article id S2211-1247(18)30991-4Article in journal (Refereed) Published
Abstract [en]

MIG6 is an important tumor suppressor that binds to and negatively regulates epidermal growth factor receptor (EGFR). Here, we report an EGFR-independent function for MIG6 as an integral component of the cell cycle machinery. We found that depletion of MIG6 causes accelerated entry into and delayed exit from mitosis. This is due to premature and prolonged activation of CDK1, a key regulator of mitotic progression at the G2/M and meta- and anaphase transitions. Furthermore, MIG6 is required for inhibition of CDK1 upon DNA damage and subsequent G2/M cell cycle arrest. Mechanistically, we found that MIG6 depletion results in reduced phosphorylation of CDK1 on the inhibitory WEE1-targeted tyrosine-15 residue. MIG6 interacts with WEE1 and promotes its stability by interfering with the recruitment of the βTrCP-SCF E3 ubiquitin ligase and consequent proteasomal degradation of WEE1. Our findings uncover a critical role of MIG6 in cell cycle progression that is likely to contribute to its potent tumor-suppressive properties.

CDK, EGFR, ERRFI1, MIG-6, RALT, WEE1, betaTrCP, cell cycle, cyclin-dependent kinase, mitosis
National Category
Cell Biology
urn:nbn:se:uu:diva-357232 (URN)10.1016/j.celrep.2018.06.064 (DOI)000440377500017 ()30067982 (PubMedID)
Swedish Research Council, 2014-03445Swedish Cancer Society, CAN 2015/752
Available from: 2018-08-14 Created: 2018-08-14 Last updated: 2018-12-06Bibliographically approved
Okochi, Y., Aratani, Y., Adissu, H. A., Miyawaki, N., Sasaki, M., Suzuki, K. & Okamura, Y. (2016). The voltage-gated proton channel Hv1/VSOP inhibits neutrophil granule release. Journal of Leukocyte Biology, 99(1), 7-19
Open this publication in new window or tab >>The voltage-gated proton channel Hv1/VSOP inhibits neutrophil granule release
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2016 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 99, no 1, p. 7-19Article in journal (Refereed) Published
Abstract [en]

Neutrophil granule exocytosis is crucial for host defense and inflammation. Neutrophils contain 4 types of granules, the exocytotic release of which is differentially regulated. This exocytosis is known to be driven by diverse mediators, including calcium and nucleotides, but the precise molecular mechanism remains largely unknown. We show in the present study that voltage-gated proton (Hv) channels are necessary for the proper release of azurophilic granules in neutrophils. On activation of NADPH oxidase by PMA and IgG, neutrophils derived from Hvcn1 gene knockout mouse exhibited greater secretion of MPO and elastase than WT cells. In contrast, release of LTF enriched in specific granules was not enhanced in these cells. The excess release of azurophilic granules in Hv1/VSOP-deficient neutrophils was suppressed by inhibiting NADPH oxidase activity and, in part, by valinomycin, a potassium ionophore. In addition, Hv1/VSOP-deficient mice exhibited more severe lung inflammation after intranasal Candida albicans infection than WT mice. These findings suggest that the Hv channel acts to specifically dampen the release of azurophilic granules through, in part, the suppression of increased positive charges at the plasma membrane accompanied by the activation of NADPH oxidase in neutrophils.

proton channel, inflammation
National Category
Medical and Health Sciences
urn:nbn:se:uu:diva-283809 (URN)10.1189/jlb.3HI0814-393R (DOI)000371890000003 ()25990245 (PubMedID)
Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2017-11-30Bibliographically approved

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