Oncogenic kinase-induced PKM2 tyrosine 105 phosphorylation converts nononcogenic PKM2 to a tumor promoter and induces cancer stem-like cells

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buir.contributor.authorŞahin, Özgür
dc.citation.epage2261en_US
dc.citation.issueNumber9en_US
dc.citation.spage2248en_US
dc.citation.volumeNumber78en_US
dc.contributor.authorZhou, Z.en_US
dc.contributor.authorLi, M.en_US
dc.contributor.authorZhang, L.en_US
dc.contributor.authorZhao, H.en_US
dc.contributor.authorŞahin, Özgüren_US
dc.contributor.authorChen, J.en_US
dc.contributor.authorZhao, J. J.en_US
dc.contributor.authorSongyang, Z.en_US
dc.contributor.authorYu, D.en_US
dc.date.accessioned2019-02-24T12:43:05Z
dc.date.available2019-02-24T12:43:05Z
dc.date.issued2018en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractThe role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss–driven mammary tumor mouse model accelerates tumor formation. Because oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas nonphosphorylated PKM2 is nononcogenic. Indeed, PKM2 was phosphorylated at tyrosine 105 (Y105) and formed oncogenic dimers in MDA-MB-231 breast cancer cells, whereas PKM2 was largely unphosphorylated and formed nontumorigenic tetramers in nontransformed MCF10A cells. PKM2 knockdown did not affect MCF10A cell growth but significantly decreased proliferation of MDA-MB-231 breast cancer cells with tyrosine kinase activation. Multiple kinases that are frequently activated in different cancer types were identified to phosphorylate PKM2-Y105 in our tyrosine kinase screening. Introduction of the PKM2-Y105D phosphomimetic mutant into MCF10A cells induced colony formation and the CD44hi/ CD24neg cancer stem–like cell population by increasing Yesassociated protein (YAP) nuclear localization. ErbB2, a strong inducer of PKM2-Y105 phosphorylation, boosted nuclear localization of YAP and enhanced the cancer stem–like cell population. Treatment with the ErbB2 kinase inhibitor lapatinib decreased PKM2-Y105 phosphorylation and cancer stem–like cells, impeding PKM2 tumor-promoting function. Taken together, phosphorylation of PKM2-Y105 by activated kinases exerts oncogenic functions in part via activation of YAP downstream signaling to increase cancer stem–like cell properties. Significance: These findings reveal PKM2 promotes tumorigenesis by inducing cancer stem-like cell properties and clarify the paradox of PKM2's dichotomous functions in tumor progression.en_US
dc.identifier.doi10.1158/0008-5472.CAN-17-2726en_US
dc.identifier.eissn1538-7445
dc.identifier.issn0008-5472
dc.identifier.urihttp://hdl.handle.net/11693/50582
dc.language.isoEnglishen_US
dc.publisherAmerican Association for Cancer Researchen_US
dc.relation.isversionofhttps://doi.org/10.1158/0008-5472.CAN-17-2726en_US
dc.source.titleCancer Researchen_US
dc.titleOncogenic kinase-induced PKM2 tyrosine 105 phosphorylation converts nononcogenic PKM2 to a tumor promoter and induces cancer stem-like cellsen_US
dc.typeArticleen_US

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