TY - JOUR
T1 - Ubiquitin-dependent regulation of Cdc42 by XIAP
AU - Murali, Arun
AU - Shin, Jaeyoung
AU - Yurugi, Hajime
AU - Krishnan, Aswini
AU - Akutsu, Masato
AU - Carpy, Alejandro
AU - Macek, Boris
AU - Rajalingam, Krishnaraj
N1 - Funding Information:
We would like to thank Alexandra Dimitrijevic for excellent technical assistance and Ms. Claudia Braun for her assistance with the IHC analysis of lung tumor nodules. Dr. Melzer for her help and advise with the animal experiments. We thank Professors John Silke and David Vaux for sharing XIAP knockout MEFs and cDNAs. This work is supported by a BIS–PLUS3 fellowship of the Boehringer Ingelheim Stiftuing to KR. KR is a Heisenberg Professor of the DFG (RA1739/4-1) and a GFK fellow.
Funding Information:
Acknowledgements. We would like to thank Alexandra Dimitrijevic for excellent technical assistance and Ms. Claudia Braun for her assistance with the IHC analysis of lung tumor nodules. Dr. Melzer for her help and advise with the animal experiments. We thank Professors John Silke and David Vaux for sharing XIAP knockout MEFs and cDNAs. This work is supported by a BIS–PLUS3 fellowship of the Boehringer Ingelheim Stiftuing to KR. KR is a Heisenberg Professor of the DFG (RA1739/4-1) and a GFK fellow.
Publisher Copyright:
© The Author(s) 2017.
PY - 2017/6
Y1 - 2017/6
N2 - 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.
AB - 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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U2 - 10.1038/CDDIS.2017.305
DO - 10.1038/CDDIS.2017.305
M3 - Article
C2 - 28661476
AN - SCOPUS:85045114729
SN - 2041-4889
VL - 8
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 6
M1 - e2900
ER -
