Fig. 1

(A) CDK5 promotes aggressive oncogenic phenotypes in breast cancer by several mechanisms. The addition of TGF-β1 activates CDK5, which phosphorylates the FAK protein at S732, resulting in changes in the actin cytoskeleton and subsequently leading to EMT and breast cancer progression. CDK5 also promotes the migration of breast cancer cells by directly phosphorylating talin (S425) and PIPKIγ90 (S453). CDK5 is also activated upon EGF stimulation, leading to adducin 1 (ADD1) phosphorylation at T724. This was followed by dynamic remodeling of the actin cytoskeleton, promoting cell migration and invasion in breast cancer. CDK5 phosphorylates PPARγ at S273, which releases ESRP1. ESRP1 is stabilized, and PPARγ is self-degraded. ESRP1 stabilization switches CD44s to the CD44v isoform, which promotes metastasis and stemness. Green and red circles show activating and inactivating phosphorylation events, respectively. (B) CDK5 promotes aggressive oncogenic phenotypes in breast cancer by inhibiting apoptosis. CDK5 depletion in breast cancer cells triggers mitochondrial permeability transition pore (mPTP) opening followed by mitochondrial depolarization and an increase in ROS production, which leads to the activation of caspases and cell death. Opening of the mPTP and mitochondrial depolarization also cause calcium release and activation of calcineurin, which causes dephosphorylation of dynamin-related protein 1 (DRP1) at S637, resulting in mitochondrial fragmentation and ultimately cell death. CDK5 knockdown also induces apoptosis in breast tumorospheres by increasing the proapoptotic protein Bim. CDK5 inhibits FOXO1 by phosphorylating it at the S249 site, favoring its nuclear export and inhibiting its transcriptional activity. In the absence of CDK5, nuclear FOXO1 thereafter induces the expression of downstream proapoptotic genes such as Bim, leading to apoptosis