FKBP51 plays an essential role in Akt ubiquitination that requires Hsp90 and PHLPP

Cell Death Dis. 2023 Feb 13;14(2):116. doi: 10.1038/s41419-023-05629-y.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HSP90 Heat-Shock Proteins* / genetics
  • HSP90 Heat-Shock Proteins* / metabolism
  • Humans
  • Melanoma* / genetics
  • Phosphoprotein Phosphatases* / genetics
  • Phosphoprotein Phosphatases* / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt* / genetics
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Signal Transduction
  • Tacrolimus Binding Proteins* / genetics
  • Tacrolimus Binding Proteins* / metabolism
  • Ubiquitination

Substances

  • Proto-Oncogene Proteins c-akt
  • tacrolimus binding protein 5
  • Tacrolimus Binding Proteins
  • HSP90 Heat-Shock Proteins
  • Phosphoprotein Phosphatases