PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1.
PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1.
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PIP4K2B是机械响应性的，可以通过UHRF1控制异染色质驱动的核软化。
DOI：
10.1038/s41467-023-37064-0
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发表时间：
2023-03-14
影响因子：
16.6
通讯作者：
Maiuri, Paolo
中科院分区：
文献类型：
--
作者：
Poli, Alessandro;Pennacchio, Fabrizio A.;Ghisleni, Andrea;di Gennaro, Mariagrazia;Lecacheur, Margaux;Nastaly, Paulina;Crestani, Michele;Pramotton, Francesca M.;Iannelli, Fabio;Beznusenko, Galina;Mironov, Alexander A.;Panzetta, Valeria;Fusco, Sabato;Sheth, Bhavwanti;Poulikakos, Dimos;Ferrari, Aldo;Gauthier, Nils;Netti, Paolo A.;Divecha, Nullin;Maiuri, Paolo
磷酸磷脂酰肌醇-5-磷酸(PtdIns5P) - 4-激酶（PIP4Ks）是一种受应激调节的磷酸肌醇激酶，能够将PtdIns5P磷酸化为PtdIns(4,5)P2。在癌症患者中，它们的表达通常与不良预后相关。在哺乳动物细胞中表达的三种PIP4K亚型中，PIP4K2B是核定位更为突出的亚型。在这里，我们揭示了PIP4K2B作为一种机械反应酶的作用。在软基质上生长的细胞中，PIP4K2B蛋白水平明显降低。它的直接沉默或药物抑制，模仿细胞对柔软的反应，引发表观遗传调控因子UHRF1的减少，并诱导核极性、核膜张力和染色质压实的变化。细胞核机械状态的这种实质性重新连接驱动YAP细胞质保留并损害其作为转录调节剂的活性，最终导致细胞扩散和运动的缺陷。由于YAP信号对于人类恶性肿瘤的发生和生长至关重要，我们的数据表明，针对PIP4K2B的潜在治疗方法可能有助于控制癌细胞机械特性的改变。PIP4Ks是在癌症中经常失调的磷酸肌苷激酶。在这里，Poli和同事们发现PIP4K2B在软底物上被下调，它的缺失导致核力学特性的改变和细胞扩散和运动的缺陷。
Phosphatidylinositol-5-phosphate (PtdIns5P)−4-kinases (PIP4Ks) are stress-regulated phosphoinositide kinases able to phosphorylate PtdIns5P to PtdIns(4,5)P2. In cancer patients their expression is typically associated with bad prognosis. Among the three PIP4K isoforms expressed in mammalian cells, PIP4K2B is the one with more prominent nuclear localisation. Here, we unveil the role of PIP4K2B as a mechanoresponsive enzyme. PIP4K2B protein level strongly decreases in cells growing on soft substrates. Its direct silencing or pharmacological inhibition, mimicking cell response to softness, triggers a concomitant reduction of the epigenetic regulator UHRF1 and induces changes in nuclear polarity, nuclear envelope tension and chromatin compaction. This substantial rewiring of the nucleus mechanical state drives YAP cytoplasmic retention and impairment of its activity as transcriptional regulator, finally leading to defects in cell spreading and motility. Since YAP signalling is essential for initiation and growth of human malignancies, our data suggest that potential therapeutic approaches targeting PIP4K2B could be beneficial in the control of the altered mechanical properties of cancer cells. PIP4Ks are phosphoinositide kinases often dysregulated in cancer. Here Poli and colleagues find that PIP4K2B is downregulated on soft substrates, and its depletion leads to altered nuclear mechanical properties and defects in cell spreading and motility.
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DOI：
10.1126/science.aba2894
发表时间：
2020-10-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lomakin AJ;Cattin CJ;Cuvelier D;Alraies Z;Molina M;Nader GPF;Srivastava N;Sáez PJ;Garcia-Arcos JM;Zhitnyak IY;Bhargava A;Driscoll MK;Welf ES;Fiolka R;Petrie RJ;De Silva NS;González-Granado JM;Manel N;Lennon-Duménil AM;Müller DJ;Piel M
通讯作者：
Piel M
影响因子：
11.2
作者：
Keune WJ;Sims AH;Jones DR;Bultsma Y;Lynch JT;Jirström K;Landberg G;Divecha N
通讯作者：
Divecha N
PI5P4K在癌症中的扩大作用：一个有前途的可毒靶。
影响因子：
3.5
作者：
Arora, Gurpreet K.;Palamiuc, Lavinia;Emerling, Brooke M.
通讯作者：
Emerling, Brooke M.
DOI：
10.1083/jcb.200907029
发表时间：
2009-11-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Llères D;James J;Swift S;Norman DG;Lamond AI
通讯作者：
Lamond AI
影响因子：
4.1
作者：
Bultsma, Yvette;Keune, Willem-Jan;Divecha, Nullin
通讯作者：
Divecha, Nullin