PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in Gliomas
PKM2 is a phosphotyrosine-binding glycolytic enzyme upregulated in many cancers, including glioma, and contributes to tumor growth by regulating cell cycle progression. We noted, however, that in multiple glioma cell lines, PKM2 knock-down resulted in an accumulation of cells in G2-M phase. Moreover...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.844861/full |
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| author | Shigeo Ohba Shigeo Ohba Yongjian Tang Yongjian Tang Tor-Christian Aase Johannessen Tor-Christian Aase Johannessen Joydeep Mukherjee |
| author_facet | Shigeo Ohba Shigeo Ohba Yongjian Tang Yongjian Tang Tor-Christian Aase Johannessen Tor-Christian Aase Johannessen Joydeep Mukherjee |
| author_sort | Shigeo Ohba |
| collection | DOAJ |
| description | PKM2 is a phosphotyrosine-binding glycolytic enzyme upregulated in many cancers, including glioma, and contributes to tumor growth by regulating cell cycle progression. We noted, however, that in multiple glioma cell lines, PKM2 knock-down resulted in an accumulation of cells in G2-M phase. Moreover, PKM2 knock-down decreased Cdk1 activity while introducing a constitutively active Cdk1 reversed the effects of PKM2 knock-down on cell cycle progression. The means by which PKM2 increases Cdk1 activity have not been described. Transient interaction of T14/Y15-phosphorylated Cdk1 with cyclin B allows Cdk7-mediated pT161 Cdk1 phosphorylation followed by cdc25C-mediated removal of pT14/Y15 and activation of Cdk1 in cycling cells. In the present course of investigation, PKM2 modulation did not influence Cdk7 activity, but phosphotyrosine binding forms of PKM2 co-immunoprecipitated with pY15-containing Cdk1-cyclinB and enhanced formation of active pT161 Cdk1-cyclin B complexes. Moreover, exogenous expression of phosphotyrosine binding forms of PKM2 reversed the effects of PKM2 knock-down on G2-M arrest. We here show that PKM2 binds and stabilize otherwise transient pY15-containing Cdk1-cyclinB complexes that in turn facilitate Cdk1-cyclin B activation and entry of cells into mitosis. These results, therefore, establish metabolic enzyme PKM2 as a direct interactor and activator of Cdk1-cyclin B complex and thereby directly controls mitotic progression and the growth of brain tumor cells. |
| first_indexed | 2024-12-10T16:04:41Z |
| format | Article |
| id | doaj.art-a1305208df1a41ea9ae4ec8ca6e8777c |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-10T16:04:41Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-a1305208df1a41ea9ae4ec8ca6e8777c2022-12-22T01:42:19ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-03-011210.3389/fonc.2022.844861844861PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in GliomasShigeo Ohba0Shigeo Ohba1Yongjian Tang2Yongjian Tang3Tor-Christian Aase Johannessen4Tor-Christian Aase Johannessen5Joydeep Mukherjee6Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Neurosurgery, Fujita Health University, Toyoake, JapanDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Neurosurgery, Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United StatesThe Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, NorwayDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United StatesPKM2 is a phosphotyrosine-binding glycolytic enzyme upregulated in many cancers, including glioma, and contributes to tumor growth by regulating cell cycle progression. We noted, however, that in multiple glioma cell lines, PKM2 knock-down resulted in an accumulation of cells in G2-M phase. Moreover, PKM2 knock-down decreased Cdk1 activity while introducing a constitutively active Cdk1 reversed the effects of PKM2 knock-down on cell cycle progression. The means by which PKM2 increases Cdk1 activity have not been described. Transient interaction of T14/Y15-phosphorylated Cdk1 with cyclin B allows Cdk7-mediated pT161 Cdk1 phosphorylation followed by cdc25C-mediated removal of pT14/Y15 and activation of Cdk1 in cycling cells. In the present course of investigation, PKM2 modulation did not influence Cdk7 activity, but phosphotyrosine binding forms of PKM2 co-immunoprecipitated with pY15-containing Cdk1-cyclinB and enhanced formation of active pT161 Cdk1-cyclin B complexes. Moreover, exogenous expression of phosphotyrosine binding forms of PKM2 reversed the effects of PKM2 knock-down on G2-M arrest. We here show that PKM2 binds and stabilize otherwise transient pY15-containing Cdk1-cyclinB complexes that in turn facilitate Cdk1-cyclin B activation and entry of cells into mitosis. These results, therefore, establish metabolic enzyme PKM2 as a direct interactor and activator of Cdk1-cyclin B complex and thereby directly controls mitotic progression and the growth of brain tumor cells.https://www.frontiersin.org/articles/10.3389/fonc.2022.844861/fullPKM2G2-M arrestCdk1cyclin Bglioma |
| spellingShingle | Shigeo Ohba Shigeo Ohba Yongjian Tang Yongjian Tang Tor-Christian Aase Johannessen Tor-Christian Aase Johannessen Joydeep Mukherjee PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in Gliomas Frontiers in Oncology PKM2 G2-M arrest Cdk1 cyclin B glioma |
| title | PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in Gliomas |
| title_full | PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in Gliomas |
| title_fullStr | PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in Gliomas |
| title_full_unstemmed | PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in Gliomas |
| title_short | PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in Gliomas |
| title_sort | pkm2 interacts with the cdk1 cyclinb complex to facilitate cell cycle progression in gliomas |
| topic | PKM2 G2-M arrest Cdk1 cyclin B glioma |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.844861/full |
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