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Role of FLCN Phosphorylation in Insulin-Mediated mTORC1 Activation and Tumorigenesis

Guoyan Wang1, Lei Chen1, Xinjian Lei1

  • 1College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 21, 2023
PubMed

Insights

Insulin signaling phosphorylates folliculin (FLCN), impacting the Rag GTPase pathway and mechanistic target of rapamycin complex 1 (mTORC1) activation. This FLCN phosphorylation is crucial for cell growth, autophagy, and tumor development, offering a potential therapeutic target.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Cancer research

Background:

  • The Rag GTPase pathway regulates mechanistic target of rapamycin complex 1 (mTORC1) activation.
  • The influence of growth factors on Rag GTPase-mediated mTORC1 activation is not well understood.

Purpose of the Study:

  • To identify and characterize the mechanism by which growth factors, specifically insulin, regulate mTORC1 activation via the Rag GTPase pathway.
  • To investigate the role of folliculin (FLCN) in this signaling cascade.

Main Methods:

  • Identification and characterization of an insulin-responsive phosphorylation site (Ser62) on FLCN.
  • Investigating the localization and recruitment of mTORC2-AKT1 to lysosomes.
  • Assessing the impact of FLCN phosphorylation on Rag GTPase activity and mTORC1 activation.
  • Evaluating the functional consequences of FLCN phosphorylation on cell viability, autophagy, and tumor growth.

Main Results:

  • Insulin signaling, via AKT1, phosphorylates FLCN at Ser62 on lysosomes.
  • This phosphorylation is dependent on RagD-specific recruitment of mTORC2-AKT1.
  • Phosphorylated FLCN inhibits RagC GTPase activity, which is essential for insulin-induced mTORC1 activation.
  • Phosphorylated FLCN enhances cell viability, induces autophagy, and regulates tumor growth in an mTORC1-dependent manner.
  • FLCN expression correlates positively with mTORC1 activity in colon cancer, clear cell renal cell carcinoma, and chordoma.

Conclusions:

  • FLCN acts as a key intermediate linking amino acid and growth factor signaling pathways to mTORC1.
  • FLCN phosphorylation is a critical step in insulin-mediated mTORC1 activation.
  • Targeting FLCN phosphorylation may offer a therapeutic strategy for diseases involving mTORC1 dysregulation, including various cancers.
Keywords:
FLCN phosphorylationinsulinmTORC1tumorigenesis

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