Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
Nat Commun. 2023 May 24;14(1):2983. doi: 10.1038/s41467-023-38740-x.
PTEN is a multifaceted tumor suppressor that is highly sensitive to alterations in expression or function. The PTEN C-tail domain, which is rich in phosphorylation sites, has been implicated in PTEN stability, localization, catalytic activity, and protein interactions, but its role in tumorigenesis remains unclear. To address this, we utilized several mouse strains with nonlethal C-tail mutations. Mice homozygous for a deletion that includes S370, S380, T382 and T383 contain low PTEN levels and hyperactive AKT but are not tumor prone. Analysis of mice containing nonphosphorylatable or phosphomimetic versions of S380, a residue hyperphosphorylated in human gastric cancers, reveal that PTEN stability and ability to inhibit PI3K-AKT depends on dynamic phosphorylation-dephosphorylation of this residue. While phosphomimetic S380 drives neoplastic growth in prostate by promoting nuclear accumulation of β-catenin, nonphosphorylatable S380 is not tumorigenic. These data suggest that C-tail hyperphosphorylation creates oncogenic PTEN and is a potential target for anti-cancer therapy.
PTEN 是一种多效性的肿瘤抑制因子，对表达或功能的改变非常敏感。富含磷酸化位点的 PTEN C 端结构域，被认为与 PTEN 的稳定性、定位、催化活性和蛋白相互作用有关，但它在肿瘤发生中的作用仍不清楚。为了解决这个问题，我们利用了几种带有非致死性 C 端突变的小鼠品系。S370、S380、T382 和 T383 缺失的纯合子小鼠含有低水平的 PTEN 和过度活跃的 AKT，但不易发生肿瘤。对含有非磷酸化或磷酸模拟 S380（人类胃癌中高度磷酸化的残基）的小鼠进行分析，揭示了 PTEN 的稳定性和抑制 PI3K-AKT 的能力取决于该残基的动态磷酸化-去磷酸化。虽然磷酸模拟 S380 通过促进β-连环蛋白的核积累来驱动前列腺的肿瘤生长，但不可磷酸化的 S380 没有致瘤性。这些数据表明 C 端过度磷酸化会产生致癌性的 PTEN，是癌症治疗的潜在靶点。
