Department of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Mol Cell Biol. 2013 Aug;33(16):3091-8. doi: 10.1128/MCB.00319-13. Epub 2013 Jun 3.
Programmed death 1 (PD-1) is a potent inhibitor of T cell responses. PD-1 abrogates activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, but the mechanism remains unclear. We determined that during T cell receptor (TCR)/CD3- and CD28-mediated stimulation, PTEN is phosphorylated by casein kinase 2 (CK2) in the Ser380-Thr382-Thr383 cluster within the C-terminal regulatory domain, which stabilizes PTEN, resulting in increased protein abundance but suppressed PTEN phosphatase activity. PD-1 inhibited the stabilizing phosphorylation of the Ser380-Thr382-Thr383 cluster within the C-terminal domain of PTEN, thereby resulting in ubiquitin-dependent degradation and diminished abundance of PTEN protein but increased PTEN phosphatase activity. These effects on PTEN were secondary to PD-1-mediated inhibition of CK2 and were recapitulated by pharmacologic inhibition of CK2 during TCR/CD3- and CD28-mediated stimulation without PD-1. Furthermore, PD-1-mediated diminished abundance of PTEN was reversed by inhibition of ubiquitin-dependent proteasomal degradation. Our results identify CK2 as a new target of PD-1 and reveal an unexpected mechanism by which PD-1 decreases PTEN protein expression while increasing PTEN activity, thereby inhibiting the PI3K/Akt signaling axis.
程序性死亡受体 1（PD-1）是 T 细胞反应的有效抑制剂。PD-1 可阻断磷脂酰肌醇 3-激酶（PI3K）/Akt 通路的激活，但具体机制尚不清楚。我们发现，在 T 细胞受体（TCR）/CD3 和 CD28 介导的刺激下，PTEN 的 C 端调节域中的丝氨酸 380-苏氨酸 382-苏氨酸 383 簇通过酪蛋白激酶 2（CK2）发生磷酸化，从而稳定了 PTEN，导致其蛋白丰度增加但磷酸酶活性受到抑制。PD-1 抑制了 PTEN C 端结构域 Ser380-Thr382-Thr383 簇的稳定磷酸化，导致其泛素依赖性降解，蛋白丰度降低，但磷酸酶活性增加。这些对 PTEN 的影响是 PD-1 介导的 CK2 抑制的结果，并且在 TCR/CD3 和 CD28 介导的刺激过程中通过药理学抑制 CK2 而重现，而无需 PD-1。此外，PD-1 介导的 PTEN 蛋白丰度降低可通过抑制泛素依赖性蛋白酶体降解来逆转。我们的结果确定 CK2 为 PD-1 的新靶点，并揭示了 PD-1 降低 PTEN 蛋白表达同时增加 PTEN 活性从而抑制 PI3K/Akt 信号通路的一种意外机制。
