Abstract
The activity of cullin-RING type ubiquitination E3 ligases is regulated by neddylation, a process analogous to ubiquitination that culminates in covalent attachment of the ubiquitin-like protein Nedd8 to cullins. As a component of the E3 for neddylation, SCCRO/DCUN1D1 plays a key regulatory role in neddylation and, consequently, cullin-RING ligase activity. The essential contribution of SCCRO to neddylation is to promote nuclear translocation of the cullin-ROC1 complex. The presence of a myristoyl sequence in SCCRO3, one of four SCCRO paralogues present in humans that localizes to the membrane, raises questions about its function in neddylation. We found that although SCCRO3 binds to CAND1, cullins, and ROC1, it does not efficiently bind to Ubc12, promote cullin neddylation, or conform to the reaction processivity paradigms, suggesting that SCCRO3 does not have E3 activity. Expression of SCCRO3 inhibits SCCRO-promoted neddylation by sequestering cullins to the membrane, thereby blocking its nuclear translocation. Moreover, SCCRO3 inhibits SCCRO transforming activity. The inhibitory effects of SCCRO3 on SCCRO-promoted neddylation and transformation require both an intact myristoyl sequence and PONY domain, confirming that membrane localization and binding to cullins are required for in vivo functions. Taken together, our findings suggest that SCCRO3 functions as a tumor suppressor by antagonizing the neddylation activity of SCCRO.
Highlights
SCCRO3/DCUN1D3 is proposed to function as a tumor suppressor
SCCRO3 Expression Is Decreased in Human Tumors—We and others have shown that amplification and overexpression of SCCRO are common in many different types of human cancer and that they underlie its function as an oncogene (21, 28 –30)
Expression of SCCRO mRNA was increased in many different tumor types studied, which is consistent with its known oncogenic activity (Fig. 1B)
Summary
SCCRO3/DCUN1D3 is proposed to function as a tumor suppressor. the mechanisms are not well defined. Results: SCCRO3 inhibits SCCRO-promoted nuclear translocation and neddylation of cullins by sequestering them to the cell membrane. The presence of a myristoyl sequence in SCCRO3, one of four SCCRO paralogues present in humans that localizes to the membrane, raises questions about its function in neddylation. The inhibitory effects of SCCRO3 on SCCRO-promoted neddylation and transformation require both an intact myristoyl sequence and PONY domain, confirming that membrane localization and binding to cullins are required for in vivo functions. Given the importance of nuclear localization in the neddylation function of SCCRO family members, the presence of a myristoyl sequence in SCCRO3 that localizes it to the membrane raises questions about its in vivo activities [17]. We show that by sequestering cullins to the membrane to prevent their nuclear translocation, SCCRO3 inhibits SCCRO-promoted neddylation and, CRL-promoted ubiquitination. The high prevalence of reduced SCCRO3 expression in multiple tumor types suggests that it plays a significant role in human cancer pathogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
