Proteasome regulation by reversible tyrosine phosphorylation at the membrane.
Proteasome regulation by reversible tyrosine phosphorylation at the membrane.
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通过膜上可逆酪氨酸磷酸化调节蛋白酶体
DOI：
10.1038/s41388-021-01674-z
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发表时间：
2021-03
期刊：
影响因子：
8
通讯作者：
Guo X
中科院分区：
文献类型：
--
作者：
Chen L;Zhang Y;Shu X;Chen Q;Wei T;Wang H;Wang X;Wu Q;Zhang X;Liu X;Zheng S;Huang L;Xiao J;Jiang C;Yang B;Wang Z;Guo X
可逆磷酸化已成为调节健康和疾病中26 S蛋白酶体功能的重要机制。人类蛋白酶体的磷酸化酪氨酸（pTyr）位点已被检测到超过100个，但它们的功能和调节仍然知之甚少。在这里，我们表明，19 S亚基Rpt 2是磷酸化的Tyr 439，一个严格保守的残基内的C-末端HbYX基序的Rpt 2是必不可少的26 S蛋白酶体组装。出乎意料的是，我们发现Y 439磷酸化依赖于Rpt 2膜定位介导的N-豆蔻酰化。多受体酪氨酸激酶（RTK）可通过激活N-肉豆蔻酰化酪氨酸激酶Src来触发Rpt 2-Y 439磷酸化。Src在体外直接磷酸化Rpt 2-Y 439并负调节细胞膜上的26 S蛋白酶体活性，这可以被蛋白酪氨酸磷酸酶非受体2型（PTPN 2）的膜相关亚型逆转。在具有活化Src的H1975肺癌细胞中，通过Y 439 F突变阻断Rpt 2-Y 439磷酸化在体外和小鼠异种移植肿瘤模型中赋予对Src抑制剂saracatinib的部分抗性，并在蛋白质组水平上引起对saracatinib的细胞应答的显著变化。我们的研究已经确定了一种新的机制，参与蛋白酶体功能的空间调控，并提供了新的见解酪氨酸激酶为基础的抗癌治疗。
Reversible phosphorylation has emerged as an important mechanism for regulating 26S proteasome function in health and disease. Over 100 phospho-tyrosine (pTyr) sites of the human proteasome have been detected, and yet their function and regulation remain poorly understood. Here we show that the 19S subunit Rpt2 is phosphorylated at Tyr439, a strictly conserved residue within the C-terminal HbYX motif of Rpt2 that is essential for 26S proteasome assembly. Unexpectedly, we found that Y439 phosphorylation depends on Rpt2 membrane localization mediated by its N-myristoylation. Multiple receptor tyrosine kinases (RTKs) can trigger Rpt2-Y439 phosphorylation by activating Src, a N-myristoylated tyrosine kinase. Src directly phosphorylates Rpt2-Y439 in vitro and negatively regulates 26S proteasome activity at cellular membranes, which can be reversed by the membrane-associated isoform of protein tyrosine phosphatase non-receptor type 2 (PTPN2). In H1975 lung cancer cells with activated Src, blocking Rpt2-Y439 phosphorylation by the Y439F mutation conferred partial resistance to the Src inhibitor saracatinib both in vitro and in a mouse xenograft tumor model, and caused significant changes of cellular responses to saracatinib at the proteome level. Our study has defined a novel mechanism involved in the spatial regulation of proteasome function and provided new insights into tyrosine kinase inhibitor-based anti-cancer therapies.
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位点特异性蛋白酶体磷酸化控制细胞增殖和肿瘤发生。
影响因子：
21.3
作者：
Guo X;Wang X;Wang Z;Banerjee S;Yang J;Huang L;Dixon JE
通讯作者：
Dixon JE
DOI：
10.1073/pnas.1716305114
发表时间：
2017-12-26
影响因子：
11.1
作者：
Albert S;Schaffer M;Beck F;Mosalaganti S;Asano S;Thomas HF;Plitzko JM;Beck M;Baumeister W;Engel BD
通讯作者：
Engel BD
影响因子：
3.2
作者：
Alevizopoulos, Konstantinos;Calogeropoulou, Theodora;Stournaras, Christos
通讯作者：
Stournaras, Christos
影响因子：
4.8
作者：
Kim, Young-Chan;DeMartino, George N.
通讯作者：
DeMartino, George N.
影响因子：
16.6
作者：
Bard JAM;Goodall EA;Greene ER;Jonsson E;Dong KC;Martin A
通讯作者：
Martin A