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.
Mesh Terms:
Actomyosin, Brain Neoplasms, Calmodulin-Binding Proteins, Cell Line, Tumor, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase Inhibitor Proteins, Cyclin-Dependent Kinases, Dual-Specificity Phosphatases, E2F Transcription Factors, Enzyme Activation, Glioblastoma, Humans, MicroRNAs, Neoplasm Invasiveness, PTEN Phosphohydrolase, Phosphorylation, Protein Binding, RNA Interference, RNA, Small Interfering, Retinoblastoma Protein, rac1 GTP-Binding Protein, rho-Associated Kinases
Oncogene
Date: Mar. 12, 2015
Download Curated Data For This Publication
199263
Switch View:
  • Interactions 6