Fig. 7

(A) Regulation of melanoma by CDK5/p35 signaling. CDK5 regulates cell invasion and metastasis by phosphorylating vimentin in melanoma. CDK5 phosphorylates vimentin at S56, causing disassembly of vimentin filaments and leading to invasion and metastasis. CDK5 activation also leads to phosphorylation of Caldesmon indirectly at Y27, which downregulates it, resulting in increased cell migration. CDK5 inhibits PD-L1 degradation, which ultimately results in enhanced tumorigenesis and metastasis. (B) CDK5 activates AKT signaling in ovarian cancer. CDK5 promotes ovarian cancer by upregulating AKT activation and inhibiting caspase-dependent apoptosis. Activation of CDK5 activates AKT, which further promotes ovarian cancer cell proliferation by inhibiting apoptosis and cell cycle arrest by preventing the nuclear translocation of p53 and p27. (C) CDK5 inhibits immune response in medulloblastomas. CDK5 inhibition decreases PD-L1 expression to induce antitumor immunity. In wild-type tumor cells, interferon gamma (IFNγ) stimulation activates IRF1-mediated transcription of PD-L1 in tumor cells. PD-L1 binds to programmed cell death 1 (PD-1) on CD4 + T cells, which inhibits the antitumor immune response and results in tumor initiation and growth. Conversely, in CDK5-deficient tumor cells, IRF2 and IRF2BP2 inhibit the induction of PD-L1 transcription by interferon regulatory factor-1 (IRF1) and result in reduced expression of PD-L1. This induces an immune response and results in tumor rejection. Green arrows represent activating pathways