Fig. 4

CDK5 promotes GBM by several mechanisms. In response to IGF-1, CDK5 phosphorylates PIKE-A at two different sites and stimulates its GTPase activity, which activates nuclear AKT and promotes glioblastoma cell proliferation and migration. Similarly, EGFR-activated CDK5 phosphorylates TRIM59 at S308, which recruits PIN1 for cis–trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. Nuclear TRIM59 enhances STAT3 signaling and tumorigenicity by promoting macroH2A1 ubiquitination and degradation. CDK5-mediated CRMP2 phosphorylation at S522 is another important event that drives glioblastoma cell proliferation. In addition, CDK5 phosphorylates cortactin, which decreases the actin-bundling activity of the dynamin1-cortactin complex, resulting in enhanced cell migration. OGT activates CDK5 by O-GlcNAcylation (OGlc), which in turn phosphorylates acetyl-CoA synthetase 2 (ACSS2) at S267, inhibiting its degradation in GBM cells. ACSS2 converts acetate to acetyl-CoA, which in turn supports tumorigenesis. CDK5 phosphorylates DRP1 at S616, activating it and leading to increased mitochondrial fission