PXD033828

PXD033828 is an original dataset announced via ProteomeXchange.

Title	The role of FKBP51 in the activation of Akt oncogenic pathway
Description	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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:43:07.694.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	CHIARA D'AMBROSIO
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2022-05-12 02:19:24	ID requested
1	2023-03-11 06:08:52	announced
⏵ 2	2023-11-14 08:43:09	announced	2023-11-14: Updated project metadata.

Tufano M, Marrone L, D'Ambrosio C, Di Giacomo V, Urzini S, Xiao Y, Matuozzo M, Scaloni A, Romano MF, Romano S, FKBP51 plays an essential role in Akt ubiquitination that requires Hsp90 and PHLPP. Cell Death Dis, 14(2):116(2023) [pubmed]

submitter keyword: LC-MS-MS,FKBP51, interactome

Andrea Scaloni
contact affiliation	Proteomics, Metabolomics & Mass Spectrometry Laboratory, Institute for the Animal Production System in the Mediterranean Environment (ISPAAM), National Research Council, Piazzale Enrico Fermi 1, 80055 Portici (NA), Italy
contact email	andrea.scaloni@cnr.it
lab head
CHIARA D'AMBROSIO
contact affiliation	ISPAAM CNR
contact email	chiara.dambrosio@cnr.it
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/03/PXD033828

PRIDE project URI

• PRIDE
  1. PXD033828
     1. Label: PRIDE project
     2. Name: The role of FKBP51 in the activation of Akt oncogenic pathway