Pathway link FLCN-RAG

FLCN / FNIP1/2 → Rag GTPases

FLCN / FNIP1/2 activates Rag GTPases.

FLCN helps set the other half of the Rag pair (RagC/D) into its working shape: it makes RagC/D break down its bound GTP, the cell's energy-carrying molecule. So 'activates' here means it sets the state of that one half, not that it switches on every Rag. Its direct job is mainly to control one group of outputs (TFEB and TFE3) rather than the whole pathway, but in kidney and lung, losing FLCN can still end up over-activating mTORC1 through a feedback loop.

FLCN-FNIP is the GAP for RagC/D: it makes RagC/D hydrolyse its bound GTP, which puts that half of the Rag dimer into the GDP-bound state. 'Activates' on this edge means exactly that: FLCN-FNIP sets the nucleotide state of RagC/D. It does not switch on every Rag. The dimer can hold mTORC1 only when both halves are in the right state (RagA/B GTP-bound and RagC/D GDP-bound), and other factors act on the RagA/B half. Its direct effect is SUBSTRATE-SPECIFIC: it gates TFEB and TFE3 phosphorylation, while canonical outputs like S6K1 and 4E-BP1 largely carry on without it in the short term.

The conditions it holds under

FLCN's direct effect is substrate-specific: losing it blocks mTORC1 phosphorylation of TFEB/TFE3 while leaving S6K1 and 4E-BP1 largely intact in the short term (NAP2020). That is not the whole of Birt-Hogg-Dube, though. Constitutively active TFEB/TFE3 drive a feedback loop that hyperactivates mTORC1, and in kidney and lung that mTORC1 hyperactivation is itself a key driver of cyst and tumour formation (Di Malta 2023, EMBO Mol Med, PMID 36987696; Ferniani 2026, FER2026 in corpus; Cao 2026, JCI, PMID 41697734, 3 BHD patient lungs + mouse). So the regulation is tissue- and time-dependent, not a flat absence of hyperactivation.

Time it takes

seconds

Step

direct (one molecule acts on the other)

Measured in

human cells

Where in the cell

lysosome

Reaches people?

plausible in people, not shown directly

How settled

settled in the literature

Studies behind it

Points the other way

No study in the Atlas contradicts this link. That means none in this curated set, not none in the literature.

Who has checked this

Checked by

No researcher outside the project has checked this link yet.

Curator sign-off

Not signed off yet. This link was drafted with AI help and has not been reviewed link by link; treat it as a proposal until it is.

Curated by

Oliver Barton, with AI help for drafting; see how links are checked.

The source works as a GAP: it changes the GTP or GDP state of the target. The label says what that does to the target, not that the target is switched on or off everywhere.

“How settled” describes how far researchers in the field agree. It is not the same as the sign-off above, which only says whether a named curator has checked this page.

If this link rests on your own work: a click on “This looks right” below, or a short note through “Report an error”, helps us more than anything else on this page.

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