An Anti-Invasive Role for Mdmx through the RhoA GTPase under the Control of the NEDD8 Pathway.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

rhoA GTP-Binding Protein*/metabolism ; NEDD8 Protein*/metabolism; Humans ; Animals ; Proto-Oncogene Proteins/metabolism ; Signal Transduction/drug effects ; Cell Movement/drug effects ; Tumor Suppressor Protein p53/metabolism ; Pyrimidines/pharmacology ; Cell Cycle Proteins/metabolism ; Proto-Oncogene Proteins c-mdm2/metabolism ; Cullin Proteins/metabolism ; Neoplasm Invasiveness ; Gastrulation ; Proteolysis/drug effects ; Cyclopentanes/pharmacology ; Cyclopentanes/metabolism

Mdmx (Mdm4) is established as an oncogene mainly through repression of the p53 tumour suppressor. On the other hand, anti-oncogenic functions for Mdmx have also been proposed, but the underlying regulatory pathways remain unknown. Investigations into the effect of inhibitors for the NEDD8 pathway in p53 activation, human cell morphology, and in cell motility during gastrulation in Xenopus embryos revealed an anti-invasive function of Mdmx. Through stabilisation and activation of the RhoA GTPase, Mdmx is required for the anti-invasive effects of NEDDylation inhibitors. Mechanistically, through its Zn finger domain, Mdmx preferentially interacts with the inactive GDP-form of RhoA. This protects RhoA from degradation and allows for RhoA targeting to the plasma membrane for its subsequent activation. The effect is transient, as prolonged NEDDylation inhibition targets Mdmx for degradation, which subsequently leads to RhoA destabilisation. Surprisingly, Mdmx degradation requires non-NEDDylated (inactive) Culin4A and the Mdm2 E3-ligase. This study reveals that Mdmx can control cell invasion through RhoA stabilisation/activation, which is potentially linked to the reported anti-oncogenic functions of Mdmx. As inhibitors of the NEDD8 pathway are in clinical trials, the status of Mdmx may be a critical determinant for the anti-tumour effects of these inhibitors.

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Keywords: Mdmx; NEDD8; RhoA; cell invasion; cell migration

EC 3.6.5.2 (rhoA GTP-Binding Protein)
0 (NEDD8 Protein)
0 (NEDD8 protein, human)
0 (MDM4 protein, human)
0 (Proto-Oncogene Proteins)
0 (Tumor Suppressor Protein p53)
S3AZD8D215 (pevonedistat)
124671-05-2 (RHOA protein, human)
0 (Pyrimidines)
0 (Cell Cycle Proteins)
EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
0 (Cullin Proteins)
0 (Cyclopentanes)

Date Created: 20241015 Date Completed: 20241015 Latest Revision: 20241018

20241018

PMC11475522

10.3390/cells13191625

39404389