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PRKAA/AMPKα phosphorylation switches the role of RASAL2 from a suppressor to an activator of autophagy

Yong Bao1,2, Christopher Qian3, Meng-Yue Liu1

  • 1Institute of Translational and Precision Medicine, Nantong University, Nantong, China.

Autophagy
|February 10, 2021
PubMed

Insights

RASAL2 regulates autophagy by controlling AMPK phosphorylation. Its S351 phosphorylation promotes breast tumor growth, suggesting therapeutic targeting for cancer treatment.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • RASAL2 (RAS protein activator like 2) is a RAS GTPase activating protein that inactivates the RAS pathway in cancer.
  • The precise cellular functions of RASAL2 are not fully understood.
  • Autophagy, a cellular degradation process, plays a complex role in cancer development and progression.

Purpose of the Study:

  • To elucidate the role of RASAL2 in regulating autophagy.
  • To investigate the mechanism by which RASAL2 influences autophagy initiation and promotion.
  • To determine the clinical significance of RASAL2 phosphorylation in breast cancer.

Main Methods:

  • Investigated RASAL2's interaction with protein phosphatase PPM1B/pp2cβ.
  • Examined the effect of glucose starvation on RASAL2 and PRKAA/AMPKα.
  • Analyzed the phosphorylation status of RASAL2 at S351 and its impact on the PIK3C3/VPS34 complex.
  • Correlated RASAL2 S351 phosphorylation with clinical outcomes in breast cancer patients.

Main Results:

  • RASAL2 inhibits basal autophagy under normal conditions by recruiting PPM1B/pp2cβ to attenuate PRKAA/AMPKα phosphorylation.
  • Glucose starvation triggers dissociation of PPM1B/pp2cβ from RASAL2, leading to PRKAA/AMPKα-mediated phosphorylation of RASAL2 at S351.
  • Phosphorylated RASAL2 enhances PIK3C3/VPS34 activity and promotes autophagy.
  • RASAL2 S351 phosphorylation is linked to increased breast tumor growth and poorer clinical outcomes in breast cancer patients.

Conclusions:

  • RASAL2 acts as a molecular switch controlling AMPK-mediated autophagy through its S351 phosphorylation status.
  • RASAL2 phosphorylation can either suppress or promote autophagy, influencing cancer progression.
  • Targeting RASAL2 S351 phosphorylation may offer a therapeutic strategy to overcome resistance to AMPK-activation agents in cancer therapy.
Keywords:
AutophagyPP1MBPRKAARASAL2breast cancer

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