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Autophagy. 2014 Feb;10(2):201-8. doi: 10.4161/auto.27198. Epub 2013 Nov 26.

Autophagy and SQSTM1 on the RHOA(d) again: emerging roles of autophagy in the degradation of signaling proteins.

Author information

1
Institute of Research on Cancer and Ageing of Nice (IRCAN); INSERM U1081; CNRS UMR7284; Nice, France; Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France; Equipe Labellisée par l'ARC; Villejuif, France; Centre Antoine Lacassagne; Nice, France.
2
Institute of Research on Cancer and Ageing of Nice (IRCAN); INSERM U1081; CNRS UMR7284; Nice, France; Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France; INSERM U895/C3M: Centre Méditerranéen de Médecine Moléculaire; Nice, France.
3
Institute of Research on Cancer and Ageing of Nice (IRCAN); INSERM U1081; CNRS UMR7284; Nice, France; Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France.
4
University of Michigan; Life Sciences Institute; Ann Arbor, MI USA.
5
Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France; Centre Antoine Lacassagne; Nice, France; Laboratoire TIRO-MATOs UMR E4320; Commissariat à l'Energie Atomique; Nice, France.
6
Institute of Research on Cancer and Ageing of Nice (IRCAN); INSERM U1081; CNRS UMR7284; Nice, France; Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France; Equipe Labellisée par l'ARC; Villejuif, France; Centre Antoine Lacassagne; Nice, France; Centre Hospitalier Universitaire de Nice; Pasteur Hospital; Laboratory of Clinical and Experimental Pathology; Nice, France.

Abstract

Degradation of signaling proteins is one of the most powerful tumor-suppressive mechanisms by which a cell can control its own growth, its survival, and its motility. Emerging evidence suggests that autophagy limits several signaling pathways by degrading kinases, downstream components, and transcription factors; however, this often occurs under stressful conditions. Our recent studies revealed that constitutive autophagy temporally and spatially controls the RHOA pathway. Specifically, inhibition of autophagosome degradation induces the accumulation of the GTP-bound form of RHOA. The active RHOA is sequestered via SQSTM1/p62 within autolysosomes, and accordingly fails to localize to the spindle midbody or to the cell surface, as we demonstrate herein. As a result, all RHOA-downstream responses are deregulated, thus driving cytokinesis failure, aneuploidy and motility, three processes that directly have an impact upon cancer progression. We therefore propose that autophagy acts as a degradative brake for RHOA signaling and thereby controls cell proliferation, migration, and genome stability.

KEYWORDS:

RHOA; aneuploidy; autophagy; cytokinesis; migration; tumor suppression

PMID:
24300375
PMCID:
PMC5396087
DOI:
10.4161/auto.27198
[Indexed for MEDLINE]
Free PMC Article

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