COP9 signalosome complex subunit 5 (COPS5) (COPS5)

The Jab1/p21 pathway refers to the regulatory axis where Jun activation domain-binding protein 1 (Jab1), also known as COP9 signalosome complex subunit 5 (COPS5), mediates the degradation of the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1) [1, 2]. Jab1 acts as the catalytic subunit of the COP9 signalosome, possessing isopeptidase activity that removes Nedd8 from Cullin-RING ligases (CRLs), a process essential for CRL recycling and subsequent substrate ubiquitination [3]. In various malignancies, Jab1 is frequently overexpressed, leading to the accelerated proteasomal degradation of p21, which normally functions to induce cell cycle arrest in response to DNA damage [4]. Consequently, the Jab1/p21 axis is a significant driver of uncontrolled cell proliferation and tumor progression. Therapeutic targeting of this pathway primarily focuses on small-molecule inhibitors of Jab1's metalloprotease activity, such as CSN5i-3, which stabilize p21 and other tumor suppressors like p27 and p53 [3]. While these inhibitors show potent anti-tumor activity in preclinical models, the central role of the COP9 signalosome in maintaining cellular protein homeostasis poses challenges regarding potential systemic toxicity and the need for precise patient stratification [3, 4].

Other names

Jun activation domain-binding protein 1Jab1CSN5SGN5Jab1/p21 axis

Inhibition of the isopeptidase activity of the COP9 signalosome subunit 5, preventing the deneddylation of Cullin-RING ligases and leading to the stabilization of substrates like p21 [3].