Ubiquitin-dependent regulation of Cdc42 by XIAP

  • Rho GTPases control fundamental cellular processes and Cdc42 is a well-studied member of the family that controls filopodia formation and cell migration. Although the regulation of Cdc42 activity by nucleotide binding is well documented, the mechanisms driving its proteostasis are not clear. Here, we demonstrate that the highly conserved, RING domain containing E3 ubiquitin ligase XIAP controls the protein stability of Cdc42. XIAP binds to Cdc42 and directly conjugates poly ubiquitin chains to the Lysine 166 of Cdc42 targeting it for proteasomal degradation. Depletion of XIAP led to an increased protein stability and activity of Cdc42 in normal and tumor cells. Consistently, loss of XIAP enhances filopodia formation in a Cdc42-dependent manner and this phenomenon phenocopies EGF stimulation. Further, XIAP depletion promotes lung colonization of tumor cells in mice in a Cdc42-dependent manner. These observations shed molecular insights into ubiquitin-dependent regulation of Cdc42 and that of actin cytoskeleton.

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Author:Arun Murali, Jaeyoung Shin, Hajime Yurugi, Aswini Krishnan, Masato Akutsu, Alejandro Carpy, Boris Macek, Krishnaraj Rajalingam
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/28661476
Parent Title (English):Cell death & disease
Publisher:Nature Publishing Group
Place of publication:London [u. a.]
Contributor(s):G. Melino
Document Type:Article
Year of Completion:2017
Date of first Publication:2017/06/29
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/04/17
Issue:6, e2900
Page Number:10
First Page:1
Last Page:10
Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Institutes:Biowissenschaften / Biowissenschaften
Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Licence (German):License LogoCreative Commons - Namensnennung 4.0