FKBP51 在 Akt 泛素化中发挥重要作用，该过程需要 HSP90 和 PHLPP。
FKBP51 plays an essential role in Akt ubiquitination that requires Hsp90 and PHLPP.
机构信息
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131, Naples, Italy.
Proteomics, Metabolomics and Mass Spectrometry Laboratory Institute for Animal Production Systems in Mediterranean Environments (ISPAAM), National Research Council (CNR), Piazzale Enrico Fermi 1, Portici, 80055, Naples, Italy.
出版信息
Cell Death Dis. 2023 Feb 13;14(2):116. doi: 10.1038/s41419-023-05629-y.
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.
FKBP51 在维持癌细胞，特别是黑色素瘤细胞方面起着重要作用。这种共伴侣参与了几种信号通路。FKBP51 与 Akt 和 PHLPP 形成复合物，据报道，该复合物可以使 Akt 去磷酸化。鉴于最近发现了一种剪接的 FKBP51 同工型，在本文中，我们研究了调节 Akt 激活的经典同工型和剪接同工型。我们表明，FKBP51 的 TPR 结构域介导 Akt 的 K63 泛素化，这是 Akt 激活的一个必要步骤。缺少这种结构域的剪接 FKBP51 不能将 K63-Ub 残基与 Akt 连接起来。出乎意料的是，PHLPP 的沉默并没有促进 Akt 的磷酸化，而过表达 PHLPP 甚至会诱导 Akt 的磷酸化。PHLPP 稳定了 E3 泛素连接酶 TRAF6 的水平，并支持 Akt 的 K63 泛素化。来自黑色素瘤细胞的 FKBP51 的相互作用组图谱突出了 PHLPP 在改善致癌特征，特别是细胞增殖方面的重要作用。
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