Fig. 6

(A) Molecular mechanisms of CDK5 regulation in lung cancer. Achaete-scute homolog 1 (ASH1) increases the transcription of p35 to activate CDK5, resulting in increased migration and invasion. miR-142-5p represses CDK5 expression by binding to its 3’-UTR. In lung cancer, TTN-AS1 lncRNA sponges miR-142-5p to upregulate CDK5 transcription. (B) CDK5 promotes lung tumorigenesis, metastasis, radioresistance and chemoresistance. Active CDK5 phosphorylates four serine residues in the N-terminal half of DLC1. The phosphorylation of DLC1 by CDK5 changes DLC1 from a closed conformation to an open conformation, which facilitates strong talin and tensin binding and its localization to focal adhesion. This activates the Rho-GAP activity of DLC1, which inactivates Rho GTPases, thereby inhibiting cell migration and tumor growth. Cyclase-associated protein 1 (CAP1) plays an important role in cell movement and morphological changes by acting synergistically with cofilin to regulate cytoskeleton movement. CDK5 knockdown decreased CAP1 phosphorylation followed by a reduction in proliferation and migration, suggesting that CDK5 is an upstream regulator of CAP1. Ionizing radiation or cisplatin treatment induces phosphorylation of FBXO22 at S160 or S162, which activates it, leading to PD-L1 ubiquitylation and causing increased sensitivity to DNA damaging agents. CDK5 inhibition enhances FBXO22 levels resulting in PD-L1 degradation and increased sensitivity to DNA damage. Similarly, CDK5 inhibition causes PD-L1 degradation via TRIM21 resulting in suppressed tumor growth and antitumor immunity. CDK5 activates the Hippo-TAZ signaling pathway, leading to oncogenesis and radioresistance in lung cancer