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NUAK1 coordinates growth factor-dependent activation of mTORC2 and Akt signaling

Mario Palma1, Elizabeth Riffo2, Alejandro Farias2

  • 1Laboratorio de Transducción de Señales y Cáncer, Departamento de Bioquímica y Biología Molecular, Facultad Cs. Biológicas, Universidad de Concepción, Concepción, Chile. mpalma@hsph.harvard.edu.

Cell & Bioscience
|December 22, 2023
PubMed
Abstract

Insights

NUAK1 kinase regulates growth factor-activated Akt signaling by controlling mTORC2 localization and directly phosphorylating Akt. Targeting NUAK1 may treat cancers with hyperactivated Akt signaling.

Area of Science:

  • Cellular Biology
  • Molecular Oncology

Background:

  • The mechanistic target of rapamycin complex 2 (mTORC2) pathway is crucial for cell growth, survival, and cytoskeletal organization.
  • While mTORC2 activates Akt kinase, the precise mechanisms regulating Akt activity and its crosstalk with other signaling pathways upon growth factor stimulation remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of NUAK1 in regulating growth factor-dependent Akt activation and signaling.
  • To investigate the molecular mechanisms by which NUAK1 influences Akt activity and downstream targets.
  • To assess the therapeutic potential of targeting NUAK1 in cancer.

Main Methods:

  • Investigated NUAK1's interaction with mTORC2 components and its effect on mTOR localization.
  • Assessed NUAK1's direct phosphorylation of Akt at Ser-473.
  • Analyzed the impact of NUAK1 on specific Akt substrates like FOXO1/3a and TSC2.
  • Examined NUAK1's subcellular localization using cell imaging techniques.
  • Evaluated the role of the NUAK1-Akt axis in regulating gene expression and cancer cell survival upon epidermal growth factor receptor (EGFR) stimulation.
  • Tested the efficacy of pharmacological inhibition of NUAK1 alone and in combination with Akt or mTOR inhibitors.
  • Correlated NUAK1 expression with EGFR and Akt phosphorylation in human cancer tissues.

Main Results:

  • NUAK1 regulates growth factor-dependent Akt activation through two mechanisms: controlling mTORC2 localization and directly phosphorylating Akt at Ser-473.
  • NUAK1 specifically phosphorylates Akt substrates FOXO1/3a but not TSC2, correlating with its association with early endosomes.
  • The NUAK1-Akt/FOXO1/3a axis regulates the expression of p21CIP1, p27KIP1, and FoxM1, impacting cancer cell survival upon EGFR stimulation.
  • Pharmacological inhibition of NUAK1 enhanced cell death induced by Akt or mTOR inhibitors.
  • NUAK1 expression positively correlates with EGFR expression and Akt Ser-473 phosphorylation in human cancers.

Conclusions:

  • NUAK1 kinase controls mTOR subcellular localization and directly induces Akt phosphorylation, thereby regulating growth factor-dependent Akt signaling.
  • Targeting NUAK1, alone or in combination with Akt or mTOR inhibitors, presents a potential therapeutic strategy for cancers exhibiting hyperactivated Akt signaling.
Keywords:
AktCancer signalingCo-targetingNUAK1mTORC2

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