Folliculin Contributes to VHL Tumor Suppressing Activity in Renal Cancer through Regulation of Autophagy

Bastola, Prabhat; Stratton, Yiwen; Kellner, Emily; Mikhaylova, Olga; Sartor, Maureen A.; Medvedovic, Mario; Biesiada, Jacek; Meller, Jarosław; Czyzyk-Krzeska, Maria F.

doi:10.1371/journal.pone.0070030

Cited by 23 publications

(28 citation statements)

References 14 publications

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“…While in most cell-based systems acute loss of FLCN inhibits mTORC1 activation (Bastola et al, 2013; Hartman et al, 2009; Hudon et al, 2010; Takagi et al, 2008; van Slegtenhorst et al, 2007), deletion of FLCN in tissues in vivo, causes mTORC1 hyperactivation (Baba et al, 2008; Baba et al, 2012; Chen et al, 2008; Hasumi et al, 2009) (see Discussion for more details). In the cell-based assays we have used to study other mTORC1 components, we find that FLCN is indeed necessary for mTORC1 activation by amino acids.…”

Section: Resultsmentioning

confidence: 99%

The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1

et al. 2013

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SUMMARY The mTORC1 kinase is a master growth regulator that senses numerous environmental cues, including amino acids. The Rag GTPases interact with mTORC1 and signal amino acid sufficiency by promoting the translocation of mTORC1 to the lysosomal surface, its site of activation. The Rags are unusual GTPases in that they function as obligate heterodimers, which consist of RagA or B bound to RagC or D. While the loading of RagA/B with GTP initiates amino acid signaling to mTORC1, the role of RagC/D is unknown. Here, we show that RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur. We identify FLCN and its binding partners, FNIP1/2, as Rag-interacting proteins with GAP activity for RagC/D, but not RagA/B. Thus, we reveal a role for RagC/D in mTORC1 activation and a molecular function for the FLCN tumor suppressor.

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Section: Resultsmentioning

confidence: 99%

The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1

et al. 2013

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“…Crystallographic studies have shown that the C terminus of FLCN may be distantly related to Differentially Expressed in Normal Cells and Neoplasia (DENN) domain proteins and may possess guanine nucleotide exchange factor activity toward RAB35 (16). FLCN modulates TFE3 localization (17), which may play an important role in the exit of stem cells from pluripotency (18), and interacts with other signaling pathways including the von Hippel-Lindau-hypoxia inducible factor-vascular endothelial growth factor axis (19)(20)(21), the TGF-beta pathway (22,23), Rho A signaling (24,25), cell cycle regulation (26,27), Rag-mediated amino acid sensing (28,29), and autophagy (30,31). These findings underscore FLCN as an important molecule, inactivation of which affects multiple pathways.…”

Section: Significancementioning

confidence: 99%

Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn

Hasumi

Lang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1, FNIP2) are homologous binding partners of FLCN, a tumor suppressor for kidney cancer. Recent studies have revealed potential functions for Flcn in kidney; however, kidney-specific functions for Fnip1 and Fnip2 are unknown. Here we demonstrate that Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. We observed no detectable phenotype in Fnip2 knockout mice, whereas Fnip1 deficiency produced phenotypes similar to those seen in Flcn-deficient mice in multiple organs, but not in kidneys. We found that absolute Fnip2 mRNA copy number was low relative to Fnip1 in organs that showed phenotypes under Fnip1 deficiency but was comparable to Fnip1 mRNA copy number in mouse kidney. Strikingly, kidney-targeted Fnip1/Fnip2 double inactivation produced enlarged polycystic kidneys, as was previously reported in Flcn-deficient kidneys. Kidney-specific Flcn inactivation did not further augment kidney size or cystic histology of Fnip1/Fnip2 double-deficient kidneys, suggesting pathways dysregulated in Flcn-deficient kidneys and Fnip1/Fnip2 double-deficient kidneys are convergent. Heterozygous Fnip1/homozygous Fnip2 double-knockout mice developed kidney cancer at 24 mo of age, analogous to the heterozygous Flcn knockout mouse model, further supporting the concept that Fnip1 and Fnip2 are essential for the tumor-suppressive function of Flcn and that kidney tumorigenesis in human Birt–Hogg–Dubé syndrome may be triggered by loss of interactions among Flcn, Fnip1, and Fnip2. Our findings uncover important roles for Fnip1 and Fnip2 in kidney tumor suppression and may provide molecular targets for the development of novel therapeutics for kidney cancer.

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“…Inactivating mutations in FLCN , the GAP for RagC/D, cause the Birt–Hogg–Dubé (BHD) tumor syndrome characterized by benign tumors of the hair follicles and, in some cases, kidney tumors [105–107]. Suppression of FLCN in cell based systems results in mTORC1 inactivation, consistent with its role as a positive regulator of the mTOR pathway [108–112]. However, kidney tumors derived from BHD patients have hyperactive mTORC1 signaling [113–115].…”

Section: Regulation Of Growth By Mtorc1mentioning

confidence: 99%

Amino acid management in cancer

Tsun

Possemato

2015

Seminars in Cell & Developmental Biology

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Amino acids have a dual role in cellular metabolism, as they are both the building blocks for protein synthesis and intermediate metabolites which fuel other biosynthetic reactions. Recent work has demonstrated that deregulation of both arms of amino acid management are common alterations seen in cancer. Among the most highly consumed nutrients by cancer cells are the amino acids glutamine and serine, and the biosynthetic pathways that metabolize them are required in various cancer subtypes and the object of current efforts to target cancer metabolism. Also altered in cancer are components of the machinery which sense amino acid sufficiency, nucleated by the mechanistic target of rapamycin (mTOR), a key regulator of cell growth via modulation of key processes including protein synthesis and autophagy. The precise ways in which altered amino acid management supports cellular transformation remain mostly elusive, and a fuller mechanistic understanding of these processes will be important for efforts to exploit such alterations for cancer therapy.

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Folliculin Contributes to VHL Tumor Suppressing Activity in Renal Cancer through Regulation of Autophagy

Cited by 23 publications

References 14 publications

The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1

The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1

Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn

Amino acid management in cancer

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