Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling
Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling
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DOI：
10.1073/pnas.0603781103
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发表时间：
2006-10-17
影响因子：
11.1
通讯作者：
Zbar, Berton
中科院分区：
文献类型：
--
作者：
Baba, Masaya;Hong, Seung-Beom;Zbar, Berton
Birt-Hogg-Dube综合征是一种以毛囊良性肿瘤、肺囊肿和肾肿瘤为特征的错构瘤疾病，由BHD（FLCN）基因的种系突变引起，该基因编码一种功能未知的肿瘤抑制蛋白卵泡素（FLCN）。由负责其他几种错构瘤综合征的基因编码的肿瘤抑制蛋白，LKB 1，TSC 1/2和PTEN，已被证明参与哺乳动物雷帕霉素靶蛋白（mTOR）信号通路。在这里，我们报告的FLCN相互作用的蛋白质，FNIP 1的鉴定，并证明其与5'AMP激活的蛋白激酶（AMPK），一个关键的能量传感分子，负调节mTOR活性的相互作用。FNIP 1被AMPK磷酸化，其磷酸化被AMPK抑制剂降低，这导致FNIP 1表达降低。AMPK抑制剂也减少FLCN磷酸化。此外，FLCN磷酸化减少雷帕霉素和氨基酸饥饿和促进FNIP 1过表达，表明FLCN可能是由mTOR和AMPK信号调节。我们的数据表明，在Birt-Hogg-Dube综合征中突变的FLCN及其相互作用伴侣FNIP 1可能通过AMPK和mTOR信号通路参与能量和/或营养感测。
Birt-Hogg-Dube syndrome, a hamartoma disorder characterized by benign tumors of the hair follicle, lung cysts, and renal neoplasia, is caused by germ-line mutations in the BHD(FLCN) gene, which encodes a tumor-suppressor protein, folliculin (FLCN), with unknown function. The tumor-suppressor proteins encoded by genes responsible for several other hamartoma syndromes, LKB1, TSC1/2, and PTEN, have been shown to be involved in the mammalian target of rapamycin (mTOR) signaling pathway. Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK), a key molecule for energy sensing that negatively regulates mTOR activity. FNIP1 was phosphorylated by AMPK, and its phosphorylation was reduced by AMPK inhibitors, which resulted in reduced FNIP1 expression. AMPK inhibitors also reduced FLCN phosphorylation. Moreover, FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN may be regulated by mTOR and AMPK signaling. Our data suggest that FLCN, mutated in Birt-Hogg-Dube syndrome, and its interacting partner FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways.