The role of FKBP51 in the activation of Akt oncogenic pathway

ABSTRACT: FKBP51 is an immunophilin with a relevant role in sustaining cancer cell growth and aggressiveness, particularly in melanoma. Thanks to its scaffold and isomerase activities, mediated by its TPR and FK1 domains, respectively, FKBP51 participates in several signaling pathways. Akt is a serine-threonine kinase that is constitutively active in many tumors with a role in cancer growth and resistance. FKBP51 forms a complex with Akt and PH-domain leucine-rich repeat protein phosphatase (PHLPP), which is reported to deactivate Akt. The effect of FKBP51 on Akt activation is far from being fully elucidated and opposite data emerge from literature. We recently identified a spliced FKBP51 isoform. In this paper, we interrogated the two FKBP51 isoforms in the regulation of Akt activation and the underlying mechanisms. Our finding shows that the pAkt levels were upregulated by the canonical but not the spliced FKBP51. We show that the TPR domain mediates Akt-K63-ubiquitination, an essential aspect of Akt activation. The spliced FKBP51s, lacking such domain, could not link K63-Ub residues to Akt. Unexpectedly, PHLPP silencing did not foster phosphorylation of Akt, and its overexpression even induced phosphorylation of Akt. Our finding shows that PHLPP stabilizes levels of the E3-ubiquitin ligase TRAF6, a known FKBP51 interactor. We observed an increased K63-ubiquitination of Akt upon PHLPP overexpression. A mass spectrometry-based proteome profile of melanoma cells highlighted a relevant role for such phosphatase in improving oncogenic hallmarks, first, cell proliferation. In conclusion, we show that canonical FKBP51 promotes Akt activation by serving as a scaffold to build the macro complex deputed to Akt ubiquitination and phosphorylation. The short FKBP51 isoform, even if it retains the ability to bind to Akt, cannot support Akt phosphorylation, being unable to engage K63-ubiquitin.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte

DISEASE(S): Melanoma

SUBMITTER: CHIARA D'AMBROSIO  

LAB HEAD: Andrea Scaloni

PROVIDER: PXD033828 | Pride | 2023-03-11

REPOSITORIES: Pride