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FKBP51 plays an essential role in Akt ubiquitination that requires Hsp90 and PHLPP.
- Source :
-
Cell death & disease [Cell Death Dis] 2023 Feb 13; Vol. 14 (2), pp. 116. Date of Electronic Publication: 2023 Feb 13. - Publication Year :
- 2023
-
Abstract
- 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.<br /> (© 2023. The Author(s).)
- Subjects :
- Humans
Phosphorylation
Signal Transduction
Ubiquitination
Melanoma genetics
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-akt metabolism
Tacrolimus Binding Proteins genetics
Tacrolimus Binding Proteins metabolism
HSP90 Heat-Shock Proteins genetics
HSP90 Heat-Shock Proteins metabolism
Phosphoprotein Phosphatases genetics
Phosphoprotein Phosphatases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 14
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 36781840
- Full Text :
- https://doi.org/10.1038/s41419-023-05629-y