Related Experiment Video

Updated: Aug 10, 2025

Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay
06:51

Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay

Published on: July 21, 2021

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

Martina Tufano1, Laura Marrone1, Chiara D'Ambrosio2

  • 1Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131, Naples, Italy.

Cell Death & Disease
|February 13, 2023
PubMed

Insights

FKBP51 sustains melanoma by regulating Akt activation through its TPR domain. A spliced FKBP51 isoform lacking this domain cannot activate Akt, impacting cancer cell proliferation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • FKBP51 is crucial for cancer cell survival, particularly in melanoma.
  • FKBP51 interacts with Akt and PHLPP, influencing Akt signaling pathways.

Purpose of the Study:

  • Investigate the roles of canonical and spliced FKBP51 isoforms in Akt activation.
  • Elucidate the mechanism of Akt ubiquitination mediated by FKBP51.

Main Methods:

  • Utilized interactome profiling in melanoma cells.
  • Assessed Akt ubiquitination and phosphorylation.
  • Examined the impact of FKBP51 isoforms and PHLPP levels on Akt activation.

Main Results:

  • The TPR domain of FKBP51 mediates K63-linked Akt ubiquitination, essential for Akt activation.
  • Spliced FKBP51, lacking the TPR domain, fails to link K63-Ub residues to Akt.
  • PHLPP positively regulates Akt phosphorylation by stabilizing TRAF6 and promoting Akt K63-ubiquitination.
  • FKBP51 and PHLPP promote oncogenic hallmarks, including cell proliferation in melanoma.

Conclusions:

  • FKBP51's TPR domain is critical for Akt activation in melanoma via K63-ubiquitination.
  • PHLPP plays a pro-oncogenic role in melanoma by enhancing Akt activation.
  • Targeting FKBP51 and PHLPP interactions may offer therapeutic strategies for melanoma.

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