PITPNC1 Recruits RAB1B to the Golgi Network to Drive Malignant Secretion.
PITPNC1 Recruits RAB1B to the Golgi Network to Drive Malignant Secretion.
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DOI：
10.1016/j.ccell.2016.02.013
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发表时间：
2016-03-14
期刊：
影响因子：
50.3
通讯作者：
Tavazoie SF
中科院分区：
文献类型：
--
作者：
Halberg N;Sengelaub CA;Navrazhina K;Molina H;Uryu K;Tavazoie SF
致瘤效应蛋白的分泌增强是恶性细胞的特征。这一特征背后的分子和细胞机制尚不清楚。我们确定PITPNC1是一个在大部分人乳腺癌中扩增的基因，在转移性乳腺癌、黑色素瘤和结肠癌中过表达。生物化学、分子生物学和细胞生物学研究表明，PITPNC 1通过结合高尔基体常驻PI4 P和将RAB 1B定位于高尔基体来促进恶性分泌。RAB1B定位到高尔基体允许GOLPH 3募集到反式高尔基体，这有利于高尔基体延伸和增强囊泡释放。PITPNC 1介导的囊泡释放通过增加促侵袭和促血管生成介质HTRA 1、MMP 1、FAM 3C、PDGFA和ADAM 10的分泌来驱动转移。我们建立PITPNC1作为PI4P结合蛋白，增强恶性肿瘤的囊泡分泌能力。
Enhanced secretion of tumorigenic effector proteins is a feature of malignant cells. The molecular and cellular mechanisms underlying this feature are poorly defined. We identify PITPNC1 as a gene amplified in a large fraction of human breast cancer and over-expressed in metastatic breast, melanoma and colon cancer. Biochemical, molecular, and cell-biological studies reveal that PITPNC1 promotes malignant secretion by binding Golgi resident PI4P and localizing RAB1B to the Golgi. RAB1B localization to the Golgi allows for the recruitment of GOLPH3 to the trans-Golgi, which facilitates Golgi extension and enhanced vesicular release. PITPNC1-mediated vesicular release drives metastasis by increasing the secretion of pro-invasive and pro-angiogenic mediators HTRA1, MMP1, FAM3C, PDGFA, and ADAM10. We establish PITPNC1 as a PI4P-binding protein that enhances vesicular secretion capacity in malignancy.