Proteomics

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Nrf2 sequesters Keap1 preventing podosome disassembly


ABSTRACT: Nrf2 is a transcription factor playing an essential role in stress response. A knowledge of the significance of Nrf2 in cell function has not, as yet, reached out beyond transactivation of gene expression. This paper shows that GDF-15 and SDF-1-induced angiogenesis strongly depends on Nrf2 presence, but is not related to its transcriptional activity. We propose, that Nrf2 serves as a protein restraining Keap1, its known transcriptional repressor. Deficiency of Nrf2 protein available for Keap1 leads to overabundance of RhoGAP1, the protein regulating Cdc42 activity, and impairs podosome assembly, thereby indisposing actin rearrangements, preventing migration and angiogenesis. These activities can be rescued by concomitant deletion of RhoGAP1 or Keap1. We suggest that a new Nrf2 function of a Keap1 scavenger implies revising the established murine model of Nrf2 deficiency as a transcriptional knock out (tKO) mouse. The N-terminal fragment of Nrf2, containing Neh2 domain binding Keap1, is present in these animals. Thus, regarding the function of Nrf2 as a protein sequestering Keap1, both published and unpublished data on Nrf2-Keap1 duet may gain new interpretation.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Dominik Cysewski  

LAB HEAD: Anna Grochot-Przeczek

PROVIDER: PXD009161 | Pride | 2018-11-28

REPOSITORIES: pride

Dataset's files

Source:
Action DRS
7010710grocho_MOCK_5.raw Raw
7010711grocho_NRF_5.raw Raw
701072grocho_MOCK_1.raw Raw
701073grocho_NRF_1.raw Raw
701074grocho_MOCK_2.raw Raw
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Publications

Nrf2 Sequesters Keap1 Preventing Podosome Disassembly: A Quintessential Duet Moonlights in Endothelium.

Kloska Damian D   Kopacz Aleksandra A   Cysewski Dominik D   Aepfelbacher Martin M   Dulak Jozef J   Jozkowicz Alicja A   Grochot-Przeczek Anna A  

Antioxidants & redox signaling 20181025 14


<h4>Aims</h4>Nrf2 (nuclear factor erythroid 2-like 2) is a transcription factor known to modulate blood vessel formation. Various experimental settings, however, attribute to Nrf2 either stimulatory or repressive influence on angiogenesis. Our findings unveil the mechanism of Nrf2-dependent vessel formation, which reaches beyond transactivation of gene expression and reconciles previous discrepancies.<h4>Results</h4>We provide evidence that growth differentiation factor 15 (GDF-15)- and stromal  ...[more]

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