IAPs regulate the plasticity of cell migration by directly targeting Rac1 for degradation

Abstract

Inhibitors of apoptosis proteins (IAPs) are a highly conserved class of multifunctional proteins. Rac1 is a well‐studied Rho GTPase that controls numerous basic cellular processes. While the regulation of nucleotide binding to Rac1 is well understood, the molecular mechanisms controlling Rac1 degradation are not known. Here, we demonstrate X‐linked IAP (XIAP) and cellular IAP1 (c‐IAP1) directly bind to Rac1 in a nucleotide‐independent manner to promote its polyubiquitination at Lys147 and proteasomal degradation. These IAPs are also required for degradation of Rac1 upon CNF1 toxin treatment or RhoGDI depletion. Consistently, downregulation of XIAP or c‐IAP1 by various strategies led to an increase in Rac1 protein levels in primary and tumour cells, leading to an elongated morphology and enhanced cell migration. Further, XIAP counteracts Rac1‐dependent cellular polarization in the developing zebrafish hindbrain and promotes the delamination of neurons from the normal tissue architecture. These observations unveil an evolutionarily conserved role of IAPs in controlling Rac1 stability thereby regulating the plasticity of cell migration and morphogenesis.

Discoidin Domain Receptor 1 Protein Is a Novel Modulator of Megakaryocyte-Collagen Interactions

“…Thereafter, the upper side of the filters was carefully washed with cold PBS, and cells remaining on the upper face of the filters were removed with a cotton wool swab. Transwell filters were fixed in 3% paraformaldehyde for 20 min at room temperature, stained using a monoclonal antibody against CD61 and with Hoechst 33258, cut out with a scalpel, and mounted onto glass slides, putting the lower face on the top (31,32). The total number of cells that had migrated was counted, and images were acquired using a Olympus BX51 using 20ϫ/0.5 UPlanF1 objective.…”

RhoGDI SUMOylation at Lys-138 Increases Its Binding Activity to Rho GTPase and Its Inhibiting Cancer Cell Motility

“…The findings from Rajalingam and co-workers (24,25) showed that depletion of XIAP or c-IAPs led to stabilization of C-RAF and Rac1 as well as cell migration in a panel of tumor cell lines. However, in our experimental systems, we did not observe obvious reduction in Rac1 expression in HCT116 XIAP Ϫ/Ϫ cells.…”

The Rac1 hypervariable region in targeting and signaling

“…[91][92][93] Interestingly, Caveolin1 binds to XIAP in the context of VEGF-induced cell survival of endothelial cells. 94 XIAP also binds to Rac1, in a nucleotide-independent fashion 91 but the domain in Rac1 that is required for this association was not identified. Importantly, Caveolin1 links XIAP to integrins and FAK (Focal Adhesion Kinase), regulating integrin function and adhesion in endothelial cells.…”