Dataset Information

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): Q Exactive Plus

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

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Publications

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

Tufano Martina M Marrone Laura L D'Ambrosio Chiara C Di Giacomo Valeria V Urzini Simona S Xiao Yichuan Y Matuozzo Monica M Scaloni Andrea A Romano Maria Fiammetta MF Romano Simona S

Cell death & disease 20230213 2

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. ...[more]

PMID: 36781840

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Project description:The gene NMB0419 of Neisseria meningitidis strain MC58 encodes a putative tetratricopeptide repeats (TPR) containing protein, which was implicated in respiratory epithelial invasion. We have accordingly sought a role for NMB0419 in meningococcal adherence and invasion of human epithelial cells using Escherichia coli surrogates. In trans expression of NMB0419 promoted adherence of the E. coli strain to human epithelial cells, which showed a unique aggregative adherence pattern that was observed for pathogenic E. coli. This adherence was totally abolished by addition of D-mannose, suggesting that formation of type 1 pili on the surface of E. coli strain was solely responsible for the adherence and was facilitated by the expression of NMB0419. This was further supported by rigid pilus structures seen on the surface of NMB0419 expressing E. coli using electron microscopy. A survey of other meningococcal strains including serogroup A, B, C, W, X, Y and Z (n=3, 42, 10, 1, 1, 1, and 1, respectively) revealed that an NMB0419 homologue was present in all strains, however, encoded varying number of TPR domains from 1 to 7. E. coli with in trans expression of such a homologue (NMA2065) encoding single TPR domain also showed enhanced adherence to the level that was observed for the E. coli strain expressing NMB0419 encoding for 4 TPR domains. Nevertheless, in-frame deletion of the TPR-domain coding sequence from the expression plasmid construct reduced the E. coli adherence to the background level. Revisit of the NMB0419 mutant strain of meningococcus indicated that reduction in adherence was primarily responsible for the reduced epithelial invasion that was previously observed. Study of transcriptome profiles in E. coli using microarray showed that the most significantly up-regulated genes in NMB0419 expressing E. coli belonging to the fim operon encoding all necessary structure proteins and chaperons for type 1 pili, strongly suggesting a gene regulatory role for NMB0419. Although the mechanism yet to be explored, this is the first study to showed that TPR domains are involved in bacterial adherence and that a gene encoding single functional TPR domain produced the same phenotype as a homologue encoding multiple TPR domains did.

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