title: 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.
authors: Emmy Noether Group of the DFG, Institute of Biochemistry II, Goethe University Medical School, Frankfurt, Germany.
authors: Tripat Kaur
authors: TK
authors: Oberoi
authors: Taner
authors: T
authors: Dogan
authors: Jennifer C
authors: JC
authors: Hocking
authors: Rolf-Peter
authors: RP
authors: Scholz
authors: Juliane
authors: J
authors: Mooz
authors: Carrie L
authors: CL
authors: Anderson
authors: Christiaan
authors: C
authors: Karreman
authors: Dagmar
authors: D
authors: Meyer zu Heringdorf
authors: Gudula
authors: G
authors: Schmidt
authors: Mika
authors: M
authors: Ruonala
authors: Kazuhiko
authors: K
authors: Namikawa
authors: Gregory S
authors: GS
authors: Harms
authors: Alejandro
authors: A
authors: Carpy
authors: Boris
authors: B
authors: Macek
authors: Reinhard W
authors: RW
authors: Köster
authors: Krishnaraj
authors: K
authors: Rajalingam
mesh_terms: D000818:Animals; D017209:Apoptosis; D002465:Cell Movement / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D054875:Ubiquitination; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D015027:Zebrafish; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D020830:rac1 GTP-Binding Protein