Journal Article

Folliculin Encoded by the BHD Gene Interacts with a Binding Protein, FNIP1, and AMPK, and Is Involved in AMPK and mTOR Signaling

Burke, Terrence R., Hopkins, Ralph F., Oishi, Shinya, Gillette, William K., Hong, Seung-Beom, Schmidt, Laura S., Hartley, James L., Baba, Masaya, Nickerson, Michael L., Iwamatsu, Akihiro, Sharma, Nirmala, Esposito, Dominic, Furihata, Mutsuo, Linehan, W. Marston, Zbar, Berton, Warren, Michelle B., Zhen, Wei

2006

Overview

Birt-Hogg-Dubé 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Amino acids / AMP-Activated Protein Kinases / Animals / Antibodies / Biological Sciences / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cell culture techniques / Cell Line / Cell lines / Cloning, Molecular / Cultured cells / Disease / Enzyme Activation / Gene expression / Genes / Hamartoma / HEK293 cells / Humans / Molecular Sequence Data / Multienzyme Complexes - metabolism / Multiprotein Complexes / Mutation / Phosphorylation / Protein Binding / Protein Kinases - metabolism / Protein-Serine-Threonine Kinases - metabolism / Proteins / Proteins - genetics / Proteins - metabolism / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Signal Transduction - physiology / Syndrome / TOR Serine-Threonine Kinases / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism / Tumors / Western blotting