An ID2-dependent mechanism for VHL inactivation in cancer.
An ID2-dependent mechanism for VHL inactivation in cancer.
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DOI：
10.1038/nature16475
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发表时间：
2016-01-14
期刊：
影响因子：
64.8
通讯作者：
Lasorella A
中科院分区：
文献类型：
--
作者：
Lee SB;Frattini V;Bansal M;Castano AM;Sherman D;Hutchinson K;Bruce JN;Califano A;Liu G;Cardozo T;Iavarone A;Lasorella A
维持肿瘤干细胞的机制对肿瘤进展至关重要。ID2蛋白是包括癌症干细胞状态在内的癌症特征的基础。HIFα转录因子，尤其是HIF2α，在癌症干细胞（CSCs）中表达，并且是维持癌症干细胞（CSCs）所必需的。然而，ID2参与或驱动hf2 α在CSCs中积累的途径尚不清楚。我们报道DYRK1A和DYRK1B激酶磷酸化ID2上的苏氨酸-27 （T27）。缺氧通过DYRK1的失活来下调这种磷酸化，在缺氧条件下，DYRK1的活性被氧感应脯氨酸羟化酶PHD1刺激。ID2结合VHL泛素连接酶复合物，取代VHL相关的Cullin-2，并损害HIF2α泛素化和降解。DYRK1磷酸化ID2-T27可阻断ID2-VHL相互作用并保持HIF2α泛素化。在胶质母细胞瘤中，ID2正调节HIF2α活性。相反，DYRK1的表达升高使ID2- T27磷酸化，导致HIF2α不稳定，胶质瘤干性丧失，肿瘤生长抑制，胶质母细胞瘤患者的预后更有利。
Mechanisms that maintain cancer stem cells are crucial to tumor progression. The ID2 protein underpins cancer hallmarks including the cancer stem cell state. HIFα transcription factors, most notably HIF2α, are expressed in and required for maintenance of cancer stem cells (CSCs). However, the pathways that are engaged by ID2 or drive HIF2α accumulation in CSCs have remained unclear. We report that DYRK1A and DYRK1B kinases phosphorylate ID2 on Threonine-27 (T27). Hypoxia down regulates this phosphorylation via inactivation of DYRK1, whose activity is stimulated in normoxia by the oxygen sensing prolyl hydroxylase PHD1. ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin-2, and impairs HIF2α ubiquitylation and degradation. Phosphorylation of ID2-T27 by DYRK1 blocks ID2-VHL interaction and preserves HIF2α ubiquitylation. In glioblastoma ID2 positively modulates HIF2α activity. Conversely, elevated expression of DYRK1 phosphorylates ID2- T27, leading to HIF2α destabilization, loss of glioma stemness, inhibition of tumor growth, and a more favorable outcome for patients with glioblastoma.