KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway.
Aberrant splicing of the cyclin-dependent kinase-associated phosphatase, KAP, promotes glioblastoma invasion in a Cdc2-dependent manner. However, the mechanism by which this occurs is unknown. Here we show that miR-26a, which is often amplified in glioblastoma, promotes invasion in phosphatase and tensin homolog (PTEN)-competent and PTEN-deficient glioblastoma cells by directly downregulating KAP expression. Mechanistically, we find that KAP binds and activates ROCK2. Thus, RNA-mediated downregulation of KAP leads to decreased ROCK2 activity and this, in turn, increases Rac1-mediated invasion. In addition, the decrease in KAP expression activates the cyclin-dependent kinase, Cdk2, and this directly promotes invasion by increasing retinoblastoma phosphorylation, E2F-dependent Cdc2 expression and Cdc2-mediated inactivation of the actomyosin inhibitor, caldesmon. Importantly, glioblastoma cell invasion mediated by this pathway can be antagonized by Cdk2/Cdc2 inhibitors in vitro and in vivo. Thus, two distinct RNA-based mechanisms activate this novel KAP/ROCK2/Cdk2-dependent invasion pathway in glioblastoma.
1] Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA [2] Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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H
Li
Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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X
Jiang
Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Y
Y
Yu
Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
W
W
Huang
Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
H
H
Xing
Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
N Y
NY
Agar
Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
H W
HW
Yang
Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
B
B
Yang
Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
R S
RS
Carroll
1] Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA [2] Program in Neuro-Oncology, Dana Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
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Johnson
D000205:Actomyosin / Q000037:antagonists & inhibitors; D001932:Brain Neoplasms / Q000473:pathology; D016203:CDC2 Protein Kinase; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D054637:Dual-Specificity Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000502:physiology; D004789:Enzyme Activation; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000502:physiology; D054460:rho-Associated Kinases / Q000378:metabolism*
D000205:Actomyosin; D016203:CDC2 Protein Kinase; D002148:Calmodulin-Binding Proteins; D051357:Cyclin-Dependent Kinase 2; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D018844:Cyclin-Dependent Kinases; D054637:Dual-Specificity Phosphatases; D050684:E2F Transcription Factors; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D020830:rac1 GTP-Binding Protein; D054460:rho-Associated Kinases; C528163:MIRN26 microRNA, human; C107953:RAC1 protein, human; C515852:ROCK2 protein, human; C528899:CDK1 protein, human; C495894:CDK2 protein, human; C084429:CDKN3 protein, human; C494929:PTEN protein, human