S-phase kinase-associated protein 2-Cyclin-dependent kinase inhibitor 1B protein-protein interaction (Skp2-p27 PPI) (Skp2-p27 PPI)

The S-phase kinase-associated protein 2 (Skp2)-Cyclin-dependent kinase inhibitor 1B (p27) protein-protein interaction is a critical regulatory node in the eukaryotic cell cycle, specifically governing the G1 to S phase transition (Skaar et al., 2013). Skp2 acts as the substrate-recognition subunit of the SCFSkp2 E3 ubiquitin ligase complex, which targets the tumor suppressor p27 for polyubiquitination and subsequent proteasomal degradation only after p27 is phosphorylated at Thr187 (Carrano et al., 1999). In many human malignancies, including prostate, breast, and lung cancers, Skp2 is frequently overexpressed, leading to the depletion of p27 and resulting in uncontrolled cell proliferation and poor clinical outcomes (Frescas & Pagano, 2008). Therapeutic intervention focuses on small molecule inhibitors, such as SKP2-C25 and SZL-P1-41, which disrupt the physical binding between Skp2 and p27 or its cofactor Cks1 (Chan et al., 2013; Lin et al., 2014). By stabilizing p27, these inhibitors induce cell cycle arrest and apoptosis specifically in Skp2-overexpressing cancer cells. This interaction represents a significant target for the development of non-genotoxic anti-cancer therapies aimed at restoring endogenous tumor suppression.

Other names

Skp2-p27 interactionSCF(Skp2)-p27 interactionSkp2-p27Kip1 interactionSCF-Skp2-p27 complex interaction

Small molecule inhibitors disrupt the physical binding of p27 to the Skp2-Cks1 complex, preventing the SCF-Skp2-mediated polyubiquitination and subsequent 26S proteasomal degradation of p27 (Chen et al., 2008; Chan et al., 2013). This stabilization of p27 leads to the inhibition of Cyclin E-CDK2 and Cyclin A-CDK2 complexes, resulting in G1-phase cell cycle arrest and suppression of tumor growth.