ITPRIP promotes glioma progression by linking MYL9 to DAPK1 inhibition
ITPRIP promotes glioma progression by linking MYL9 to DAPK1 inhibition
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DOI：
10.1016/j.cellsig.2021.110062
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发表时间：
2021-07-21
影响因子：
4.8
通讯作者：
Ding, Lianshu
中科院分区：
文献类型：
--
作者：
Cao, Changchun;He, Kang;Ding, Lianshu
肿瘤抑制死亡相关蛋白激酶1（DAPK 1）的表观遗传基因沉默与恶性胶质瘤的进展有关。然而，DAPK 1在胶质瘤中的抑制机制仍然是难以捉摸的。在本研究中，我们鉴定了恶性胶质瘤细胞中存在DAPK 1-肌醇1，4，5-三磷酸受体（IP 3R）相互作用蛋白（ITPRIP）-肌球蛋白调节轻链多肽9（MYL 9）复合物。慢病毒共感染和免疫共沉淀实验表明，ITPRIP在体外与DAPK 1的死亡结构域（DD）结合。此外，分离的ITPRIP-DAPK 1相互作用在体外抑制胶质瘤肿瘤生长，但在体内不抑制。此外，敲低ITPRIP或DAPK 1损害三元复合物的形成，而MYL 9敲低不影响ITPRIP-DAPK 1协会。我们进一步发现ITPRIP将MYL 9募集到DAPK 1的激酶结构域（KD），进而阻碍MYL 9的磷酸化。因此，ITPRIP的干扰增强了DAPK 1-KD在体外和体内对胶质瘤进展的抑制作用。我们的研究结果表明，ITPRIP在抑制DAPK 1和增强恶性胶质瘤细胞的致瘤性中起着至关重要的作用。
Epigenetic gene silencing of the tumor suppressor death-associated protein kinase 1 (DAPK1) is implicated in the progression of malignant gliomas. However, the mechanism underlying the repression of DAPK1 in gliomas remains elusive. In this study, we identified the existence of DAPK1-inositol 1,4,5-trisphosphate receptor (IP3R)interacting protein (ITPRIP) -myosin regulatory light polypeptide 9 (MYL9) complex in malignant glioma cells. Lentivirus co-infection and coimmunoprecipitation showed that ITPRIP bound with the death domain (DD) of DAPK1 in vitro. Further, dissociating ITPRIP-DAPK1 interaction inhibited glioma tumor growth in vitro but not in vivo. Moreover, knockdown of ITPRIP or DAPK1 impaired the ternary complex formation, whereas MYL9 knockdown did not affect ITPRIP-DAPK1 association. We further found that ITPRIP recruited MYL9 to the kinase domain (KD) of DAPK1, and in turn impeded the phosphorylation of MYL9. Accordingly, interference of ITPRIP enhanced the suppressive effects of DAPK1-KD on glioma progression both in vitro and in vivo. Our results demonstrate that ITPRIP plays a crucial role in the inhibition of DAPK1 and enhancement of tumorigenic properties of malignant glioma cells.