CARD-Mediated Autoinhibition of cIAP1's E3 Ligase Activity Suppresses Cell Proliferation and Migration
Details
Publication Year 2011-06-10, Volume 42, Issue #5, Page 569-583
Journal Title
MOLECULAR CELL
Publication Type
Journal Article
Abstract
E3 ligases mediate the covalent attachment of ubiquitin to target proteins thereby enabling ubiquitin-dependent signaling. Unraveling how E3 ligases are regulated is important because miscontrolled ubiquitylation can lead to disease. Cellular inhibitor of apoptosis (cIAP) proteins are E3 ligases that modulate diverse biological processes such as cell survival, proliferation, and migration. Here, we have solved the structure of the caspase recruitment domain (CARD) of cIAP1 and identified that it is required for cIAP1 autoregulation. We demonstrate that the CARD inhibits activation of cIAP1's E3 activity by preventing RING dimerization, E2 binding, and E2 activation. Moreover, we show that the CARD is required to suppress cell proliferation and migration. Further, CARD-mediated autoregulation is also necessary to maximally suppress caspase-8-dependent apoptosis and vascular tree degeneration in vivo. Taken together, our data reveal mechanisms by which the E3 ligase activity of cIAP1 is controlled, and how its deregulation impacts on cell proliferation, migration and cell survival.
Publisher
CELL PRESS
Keywords
NF-KAPPA-B; ALPHA-DEPENDENT APOPTOSIS; DEATH DOMAIN SUPERFAMILY; CANCER-CELLS; UBIQUITIN LIGASES; LIVER-CANCER; IN-VIVO; CASPASE-8; COMPLEX; ACTIVATION
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2011-06-10 12:00:00
Last Modified: 0001-01-01 12:00:00
An error has occurred. This application may no longer respond until reloaded. Reload 🗙