DNA Damage Induces the Accumulation of Tiam1 by Blocking β-TrCP-dependent Degradation

Abstract

Background: DNA damage-induced activation of the Rac1/JNK cascade is required for apoptosis. Results: Upon chemotherapeutic drug treatment, Tiam1, a Rac1-specific GEF, is accumulated through inhibition of CK1/ ␤-TrCP-mediated degradation. Conclusion: DNA damage induces up-regulation of Tiam1, which contributes to Rac1/JNK activation. Significance: This work uncovers how the Rac1/JNK cascade is activated upon DNA damage signaling and subsequent apoptosis.

Degradation of Tiam1 by Casein Kinase 1 and the SCFβTrCP Ubiquitin Ligase Controls the Duration of mTOR-S6K Signaling

“…Interestingly, it has been recently reported that constitutive mTOR-S6K signaling sensitizes cells to p53-dependent cell death in response to stress conditions (33). In agreement with these studies, a recent report has shown that cells expressing the degradation-resistant Tiam1-C1199 mutant are more sensitive to DNA-damaging drug-induced apoptosis (34).…”

TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells

“…This prompted us to investigate whether TIAM1 was a component of the WNT-regulated destruction complex. By immunoprecipitating endogenous TIAM1 from cytosolic and nuclear fractions of confluent HEK293 cells, which carry a functional destruction complex, we found that TIAM1 interacted with AXIN, β-catenin, and (as shown previously by Magliozzi et al., 2014, Zhu et al., 2014, and above) βTrCP, which are established elements of the destruction complex as well as TAZ and YAP (Figure 5A). Even though low levels of TIAM1 were detected in the nucleus, TIAM1 interaction with AXIN, β-catenin, βTrCP, TAZ, and YAP was observed only in the cytoplasm of HEK293 cells.…”

CUL3-KBTBD6/KBTBD7 Ubiquitin Ligase Cooperates with GABARAP Proteins to Spatially Restrict TIAM1-RAC1 Signaling

“…However, we do not fully understand how this RAC1 activator is locally turned off again. For example, CUL1 SKP1/BTRC was shown to regulate TIAM1 (Magliozzi et al, 2014;Zhu et al, 2014), though its ubiquitylation and proteasomal degradation involved total protein amounts and not a subcellular pool of TIAM1. Our results expand the concept of spatially restricted regulation to TIAM1.…”