IAPs as E3 ligases of Rac1: shaping the move.
Inhibitors of Apoptosis Proteins (IAPs) are well-studied E3 ubiquitin ligases predominantly known for regulation of apoptosis. We uncovered that IAPs can function as a direct E3 ubiquitin ligase of RhoGTPase Rac1. cIAP1 and XIAP directly conjugate polyubiquitin chains to Lysine 147 of activated Rac1 and target it for proteasomal degradation. Consistently, loss of these IAPs by various strategies led to stabilization of Rac1 and mesenchymal mode of migration in tumor cells. IAPs also regulate Rac1 degradation upon RhoGDI1 depletion and CNF1 toxin treatment. Our observations revealed an evolutionarily conserved role of IAPs in regulating Rac1 stability shedding light on to the mechanisms behind ubiquitination-dependent inactivation of Rac1 signaling.
Emmy Noether Group of the DFG, Institute of Biochemistry II, Goethe University Medical School; Frankfurt, Germany.
Tripat Kaur
TK
Oberoi-Khanuja
Krishnaraj
K
Rajalingam
D000818:Animals; D002465:Cell Movement; D048430:Cell Shape; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D051034:Inhibitor of Apoptosis Proteins; D025801:Ubiquitin; D051636:X-Linked Inhibitor of Apoptosis Protein; D044767:Ubiquitin-Protein Ligases; D020830:rac1 GTP-Binding Protein