FKBP51 plays an essential role in Akt ubiquitination that requires Hsp90 and PHLPP.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
13 02 2023
13 02 2023
Historique:
received:
29
06
2022
accepted:
30
01
2023
revised:
28
01
2023
entrez:
13
2
2023
pubmed:
14
2
2023
medline:
16
2
2023
Statut:
epublish
Résumé
FKBP51 plays a relevant role in sustaining cancer cells, particularly melanoma. This cochaperone participates in several signaling pathways. FKBP51 forms a complex with Akt and PHLPP, which is reported to dephosphorylate Akt. Given the recent discovery of a spliced FKBP51 isoform, in this paper, we interrogate the canonical and spliced isoforms in regulation of Akt activation. We show that the TPR domain of FKBP51 mediates Akt ubiquitination at K63, which is an essential step for Akt activation. The spliced FKBP51, lacking such domain, cannot link K63-Ub residues to Akt. Unexpectedly, PHLPP silencing does not foster phosphorylation of Akt, and its overexpression even induces phosphorylation of Akt. PHLPP stabilizes levels of E3-ubiquitin ligase TRAF6 and supports K63-ubiquitination of Akt. The interactome profile of FKBP51 from melanoma cells highlights a relevant role for PHLPP in improving oncogenic hallmarks, particularly, cell proliferation.
Identifiants
pubmed: 36781840
doi: 10.1038/s41419-023-05629-y
pii: 10.1038/s41419-023-05629-y
pmc: PMC9925821
doi:
Substances chimiques
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
tacrolimus binding protein 5
EC 5.2.1.8
Tacrolimus Binding Proteins
EC 5.2.1.-
HSP90 Heat-Shock Proteins
0
Phosphoprotein Phosphatases
EC 3.1.3.16
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
116Informations de copyright
© 2023. The Author(s).
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