S-phase kinase-associated protein 2-Cyclin-dependent kinase regulatory subunit 1 complex (Skp2-Cks1)

The S-phase kinase-associated protein 2-Cyclin-dependent kinase regulatory subunit 1 (Skp2-Cks1) complex is a critical component of the SCF (Skp1-Cullin1-F-box) E3 ubiquitin ligase, specifically responsible for the recognition and degradation of the cyclin-dependent kinase inhibitor p27 (Kip1) [1.1.1, 1.2.1]. Cks1 acts as an essential adaptor protein that bridges the interaction between Skp2 and phosphorylated p27, facilitating its polyubiquitination and subsequent proteasomal destruction [1.4.1, 1.4.4]. Overexpression of Skp2 and Cks1 is frequently observed in various human malignancies, including breast, prostate, and lung cancers, where it leads to the depletion of p27 and promotes uncontrolled cell proliferation and poor prognosis [1.1.3, 1.3.1]. Targeting the Skp2-Cks1 protein-protein interface has emerged as a promising therapeutic strategy, particularly for RB1-deficient tumors that are highly dependent on this axis for survival [1.2.1, 1.2.4]. Small molecule inhibitors, such as SKPin-C1 and the C-series compounds, have been developed to disrupt this interface, thereby stabilizing p27 levels and inducing cell cycle arrest in cancer cells [1.1.1, 1.2.1]. Beyond its role in the cell cycle, the Skp2-Cks1 complex is also implicated in metabolic reprogramming, DNA damage response, and neurodegenerative conditions like Alzheimer's disease [1.3.1, 1.3.2].

Other names

Skp2-Cks1 complexSCF-Skp2-Cks1 E3 ubiquitin ligase complexSkp2-Cks1-p27 interfaceS-phase kinase-associated protein 2-Cyclin-dependent kinase regulatory subunit 1 interface

Disruption of the protein-protein interaction between Skp2 and Cks1 to prevent the recruitment and ubiquitination of p27, leading to p27 stabilization and subsequent cell cycle arrest.