S-phase kinase–associated protein 2 (SKP2)

S-phase kinase–associated protein 2 (SKP2) is a critical F-box protein subunit in the SCF E3 ubiquitin ligase complex, acting as a substrate recognition factor for proteins targeted for degradation by the proteasome. It contains an F-box domain near the N terminus and leucine-rich repeats (LRRs) that mediate protein–protein interactions. SKP2 is essential for the ubiquitin-mediated proteolysis of key cell cycle regulatory proteins, such as the cyclin-dependent kinase inhibitor p27Kip1—leading to cell cycle progression from G1 to S phase. Dysregulation or overexpression of SKP2 is associated with multiple cancers due to aberrant degradation of cell cycle inhibitors. Therapeutic targeting of SKP2, chiefly through small-molecule inhibitors, remains under preclinical development, given challenges in specificity and complexity of its interactions. SKP2 serves as both a potential therapeutic target and a biomarker in oncology settings.

Other names

SKP2 (gene/protein name)S-phase kinase–associated protein 2F-box protein Skp2

Inhibition of Skp2 prevents the ubiquitin-mediated degradation of key cell cycle inhibitors (primarily p27), promoting cell cycle arrest. Disruption of Skp2–substrate interaction impairs proteasomal degradation pathways. Transcriptional and post-translational inhibition (blocking F-box domain function, or interfering with protein–protein interactions within the SCF complex).