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AKAP13 couples GPCR signaling to mTORC1 inhibition

Shihai Zhang1,2,3,4, Huanyu Wang1,2,3, Chase H Melick1,2,3

  • 1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.

Plos Genetics
|October 21, 2021
PubMed

Insights

A-kinase anchoring protein 13 (AKAP13) inhibits mTORC1 signaling. This discovery reveals a new mechanism for controlling mTORC1 activity, potentially offering therapeutic targets for diseases like cancer.

Area of Science:

  • Cellular signaling and molecular biology
  • Cancer research and therapeutics
  • Endocrinology and metabolic diseases

Background:

  • Mammalian target of rapamycin complex 1 (mTORC1) regulates cellular processes and is often hyperactivated in diseases like cancer and type 2 diabetes.
  • While activators of mTORC1 are well-studied, endogenous inhibitors and their mechanisms remain less understood.
  • G-protein coupled receptors (GPCRs) signaling through Gαs proteins increases cyclic adenosine 3'5' monophosphate (cAMP) and activates protein kinase A (PKA).

Purpose of the Study:

  • To identify novel regulators of mTORC1 activity, focusing on inhibitory signaling pathways.
  • To elucidate the role of A-kinase anchoring protein 13 (AKAP13) in GPCR-mediated mTORC1 inhibition.
  • To investigate the functional consequences of AKAP13-mediated mTORC1 regulation in cancer.

Main Methods:

  • Biochemical assays to identify AKAP13 as an mTORC1 binding protein.
  • In vitro and in vivo experiments to demonstrate AKAP13's scaffolding function for PKA and mTORC1.
  • Analysis of PKA-mediated phosphorylation of Raptor on Ser 791 as the inhibitory mechanism.
  • Cell proliferation, cell size, and colony formation assays to assess functional impact.
  • Correlation studies between AKAP13 expression, mTORC1 activation, patient survival, and tumor growth.

Main Results:

  • AKAP13 directly binds to mTORC1 and acts as a scaffold for PKA.
  • PKA phosphorylates Raptor on Ser 791, leading to mTORC1 inhibition.
  • AKAP13 mediates the inhibition of mTORC1-induced cell proliferation, cell size, and colony formation.
  • AKAP13 expression positively correlates with mTORC1 activation, lung adenocarcinoma patient survival, and tumor growth in vivo.

Conclusions:

  • AKAP13 is a critical mediator of mTORC1 inhibition downstream of GPCR/Gαs/cAMP/PKA signaling.
  • The AKAP13-PKA-mTORC1 axis represents a novel regulatory pathway with implications for cancer and metabolic diseases.
  • Targeting the AKAP13 pathway could offer a therapeutic strategy for diseases characterized by hyperactivated mTORC1.

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