Dynamic regulation of KIF15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancer.
Dynamic regulation of KIF15 phosphorylation and acetylation promotes focal adhesions disassembly in pancreatic cancer.
复制标题
KIF15磷酸化和乙酰化的动态调节促进胰腺癌粘着斑解体
DOI：
10.1038/s41419-022-05338-y
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发表时间：
2022-10-25
影响因子：
9
通讯作者：
Jiang, Jianxin
中科院分区：
文献类型：
--
作者：
He, Zhiwei;Wang, Jie;Xu, Jian;Jiang, Xueyi;Liu, Xinyuan;Jiang, Jianxin
胰腺癌（PC）早期易发生远处转移，这归因于肿瘤细胞具有较强的迁移能力。粘着斑更新是癌细胞转移的关键，而整合素再循环过程是粘着斑解聚的关键活化途径。为了鉴定整合素β 1循环中的关键马达蛋白，我们利用驱动蛋白家族siRNA文库筛选了整合素β 1循环中的驱动蛋白，并鉴定出驱动蛋白家族15（KIF15）是整合素β 1循环中的关键调节因子。KIF15在转移PC组织中上调，并促进PC细胞的迁移和侵袭。我们确定KIF15是介导整合素β 1/FAK信号传导的关键组分，其以FAK-Y397依赖性方式加速FA分解。KIF15以RAB11A依赖性方式募集PI3K-C2 α促进整合素β 1/FAK信号传导和FA分解。KIF15的C-末端尾部是PI3K-C2 α相互作用和RAB11A激活所必需的。此外，我们还发现SIRT1介导的KIF15乙酰化对于KIF15磷酸化是必不可少的，KIF15磷酸化是运动蛋白功能中的关键激活事件。总之，这些发现表明KIF15与PI3K-C2 α相互作用，通过以SIRT1乙酰化修饰依赖性方式控制整合素β 1的内体再循环，促进PC细胞中的FA周转，最终促进PC中的局灶性粘附周转和远处转移。
Pancreatic cancer (PC) is prone to distant metastasis in the early stage, which is attributed to the strong migration ability of tumor cells. Focal adhesion turnover is essential for cancer cell metastasis, and the integrin recycling process is a key activation pathway for focal adhesion depolymerization. To identify the key motor protein involving in the integrin β1 recycling, we screened kinesin proteins involved in integrin β1 recycling using a kinesin family siRNA library and identified kinesin family 15 (KIF15) as a key regulator. KIF15 was upregulated in metastasis PC tissues and promoted PC cell migration and invasion. We identified KIF15 as a key component mediating integrin β1/FAK signaling that accelerated FA disassembly in a FAK-Y397-dependent manner. KIF15 recruited PI3K-C2α to promote integrin β1/FAK signaling and FA disassembly in a RAB11A-dependent manner. The C-terminal tail of KIF15 is required for the PI3K-C2α interaction and RAB11A activation. In addition, we also found that SIRT1-mediated acetylation of KIF15 is essential for KIF15 phosphorylation, which is the key activation event in motor protein function. Together, these findings indicate that KIF15 interacts with PI3K-C2α to promote FA turnover in PC cells by controlling the endosome recycling of integrin β1 in a SIRT1 acetylation modification-dependent manner, eventually promoting focal adhesions turnover and distant metastasis in PC.
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影响因子：
21.3
作者：
Alanko J;Mai A;Jacquemet G;Schauer K;Kaukonen R;Saari M;Goud B;Ivaska J
通讯作者：
Ivaska J
影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1083/jcb.201707075
发表时间：
2018-06-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Spiess M;Hernandez-Varas P;Oddone A;Olofsson H;Blom H;Waithe D;Lock JG;Lakadamyali M;Strömblad S
通讯作者：
Strömblad S
DOI：
10.1016/j.bbamcr.2016.05.013
发表时间：
2016-09-01
影响因子：
5.1
作者：
Klimova, Zuzana;Braborec, Vojtech;Vomastek, Tomas
通讯作者：
Vomastek, Tomas
影响因子：
11.8
作者：
Dozynkiewicz, Marta A.;Jamieson, Nigel B.;MacPherson, Iain;Grindlay, Joan;van den Berghe, Peter V. E.;von Thun, Anne;Morton, Jennifer P.;Gourley, Charlie;Timpson, Paul;Nixon, Colin;McKay, Colin J.;Carter, Ross;Strachan, David;Anderson, Kurt;Sansom, Owen J.;Caswell, Patrick T.;Norman, Jim C.
通讯作者：
Norman, Jim C.