The mTOR Independent Function of Tsc1 and FNIPs

Sager, Rebecca; Woodford, Mark R.; Mollapour, Mehdi

doi:10.1016/j.tibs.2018.09.018

Cited by 13 publications

(15 citation statements)

References 12 publications

(16 reference statements)

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“…The tumor suppressor TSC1 is a new co-chaperone of Hsp90 that modulates Hsp90 activity and enhances Hsp90 binding to its inhibitors [17, 20]. Mutations of TSC1 have been identified in 14.5% of bladder tumors and loss of heterozygosity of TSC1 has been reported approximately 54% of bladder cancers [21–26].…”

Section: Discussionmentioning

confidence: 99%

“…We have recently identified the tumor suppressor TSC1 as a novel regulator/co-chaperone of Hsp90 important for the folding and stability of numerous kinase and non-kinase clients including Tsc2 protein (tuberin) [17]. Tsc2 protein has a GTPase-activating function and in complex with Tsc1 protein (hamartin) and possibly Hsp90 acts as a negative regulator of AMPK/mTOR signaling [18–20]. Additionally, Tsc1 assists in the deceleration of Hsp90 ATPase activity and the Hsp90 chaperone cycle, and Tsc1 expression increases Hsp90 binding to its inhibitors [17].…”

Section: Introductionmentioning

confidence: 99%

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Mutation of the co-chaperone Tsc1 in bladder cancer diminishes Hsp90 acetylation and reduces drug sensitivity and selectivity

et al. 2019

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The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that affects Hsp90 binding to its inhibitors. Highly variable mutations of TSC1 have been previously identified in bladder cancer and correlate with sensitivity to the Hsp90 inhibitors. Here we showed loss of TSC1 leads to hypoacetylation of Hsp90-K407/K419 and subsequent decreased binding to the Hsp90 inhibitor ganetespib. Pharmacologic inhibition of histone deacetylases (HDACs) restores acetylation of Hsp90 and sensitizes Tsc1-mutant bladder cancer cells to ganetespib, resulting in apoptosis. Our findings suggest that TSC1 status may predict response to Hsp90 inhibitors in patients with bladder cancer, and co-targeting HDACs can sensitize tumors with Tsc1 mutations to Hsp90 inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutation of the co-chaperone Tsc1 in bladder cancer diminishes Hsp90 acetylation and reduces drug sensitivity and selectivity

et al. 2019

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“…In this context, it is interesting to consider mTOR-independent effects of TSC loss in human monocytes. In particular, TSC1 acts as a co-chaperone of HSP90 ( 22 , 34 ), and HSP90, in turn, reportedly modulates PAMP/TLR signaling at multiple levels, including the stabilization of functional TLR receptor complexes at the plasma membrane of human monocytes/macrophages ( 35 ). Taking all these findings together, we concluded that the effects of mTORC1 on monocyte cytokine secretion are multifaceted and impact differentially on individual cytokines.…”

Section: Discussionmentioning

confidence: 99%

mTORC1 Is Not Principally Involved in the Induction of Human Endotoxin Tolerance

2020

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Endotoxin tolerance represents a safeguard mechanism for preventing detrimental prolonged inflammation and exaggerated immune/inflammatory responses from innate immune cells to recurrent harmless pathogens. On the other hand, excessive immune tolerance can contribute to pathological immunosuppression, e.g., as present in sepsis. Monocyte activation is accompanied by intracellular metabolic rearrangements that are reportedly orchestrated by the metabolic signaling node mTORC1. mTORC1-dependent metabolic re-wiring plays a major role in monocyte/macrophage polarization, but whether mTORC1 participates in the induction of endotoxin tolerance and other immune adaptive programs, such as immune training, is not clear. This connection has been difficult to test in the past due to the lack of appropriate models of human endotoxin tolerance allowing for the genetic manipulation of mTORC1. We have addressed this shortcoming by investigating monocytes from tuberous sclerosis (TSC) patients that feature a functional loss of the tumor suppressor TSC1/2 and a concomitant hyperactivation of mTORC1. Subjecting these cells to various protocols of immune priming and adaptation showed that the TSC monocytes are not compromised in the induction of tolerance. Analogously, we find that pharmacological mTORC1 inhibition does not prevent endotoxin tolerance induction in human monocytes. Interestingly, neither manipulation affected the capacity of activated monocytes to switch to increased lactic fermentation. In sum, our findings document that mTORC1 is unlikely to be involved in the induction of endotoxin tolerance in human monocytes and argue against a causal link between an mTORC1-dependent metabolic switch and the induction of immune tolerance.

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“…Finally, both FLCN and FNIP1 have been suggested as negative regulators of AMPK as depletion of FLCN has been found to constitutively activate AMPK (Possik et al, 2014(Possik et al, , 2015Yan et al, 2014;El-Houjeiri et al, 2019) and mutations affecting FNIP1 are associated with higher AMPK activity (Siggs et al, 2016), suggesting that FLCN and FNIP may cooperate to modulate AMPK. In the same way, phosphorylated FNIP1 can bind to chaperone Hsp90, which indeed, regulates proper folding of AMPK subunits and some mTORC1 pathway components, such as Raptor or mTOR itself, suggesting another function for FNIP1 in the regulation of AMPK and mTORC1 pathways (Woodford et al, 2016;Sager et al, 2018Sager et al, , 2019. All this evidence strongly suggests a role for FLCN-FNIP in coordinating cellular metabolism through its effects on both the mTORC1 and AMPK signaling pathways, however, further studies are eagerly awaited to clarify the functional relevance of the FLCN-FNIP-AMPK interaction.…”

Section: A Potential Interaction Of Flcn-fnip With Ampkmentioning

confidence: 99%

Nutrient Signaling and Lysosome Positioning Crosstalk Through a Multifunctional Protein, Folliculin

Garrido

Chs

2020

Front. Cell Dev. Biol.

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FLCN was identified as the gene responsible for Birt-Hogg-Dubé (BHD) syndrome, a hereditary syndrome associated with the appearance of familiar renal oncocytomas. Most mutations affecting FLCN result in the truncation of the protein, and therefore loss of its associated functions, as typical for a tumor suppressor. FLCN encodes the protein folliculin (FLCN), which is involved in numerous biological processes; mutations affecting this protein thus lead to different phenotypes depending on the cellular context. FLCN forms complexes with two large interacting proteins, FNIP1 and FNIP2. Structural studies have shown that both FLCN and FNIPs contain longin and differentially expressed in normal versus neoplastic cells (DENN) domains, typically involved in the regulation of small GTPases. Accordingly, functional studies show that FLCN regulates both the Rag and the Rab GTPases depending on nutrient availability, which are respectively involved in the mTORC1 pathway and lysosomal positioning. Although recent structural studies shed light on the precise mechanism by which FLCN regulates the Rag GTPases, which in turn regulate mTORC1, how FLCN regulates membrane trafficking through the Rab GTPases or the significance of the intriguing FLCN-FNIP-AMPK complex formation are questions that still remain unanswered. We discuss the recent progress in our understanding of FLCN regulation of both growth signaling and lysosomal positioning, as well as future approaches to establish detailed mechanisms to explain the disparate phenotypes caused by the loss of FLCN function and the development of BHD-associated and other tumors.

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The mTOR Independent Function of Tsc1 and FNIPs

Cited by 13 publications

References 12 publications

Mutation of the co-chaperone Tsc1 in bladder cancer diminishes Hsp90 acetylation and reduces drug sensitivity and selectivity

Mutation of the co-chaperone Tsc1 in bladder cancer diminishes Hsp90 acetylation and reduces drug sensitivity and selectivity

mTORC1 Is Not Principally Involved in the Induction of Human Endotoxin Tolerance

Nutrient Signaling and Lysosome Positioning Crosstalk Through a Multifunctional Protein, Folliculin

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