Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Mammalian target of rapamycin complex 1 (mTORC1) signaling is crucial for cell growth and metabolism.
• Constitutive mTORC1 activation is a hallmark of many cancers, driving oncogenic processes.
• Pyruvate kinase M2 (PKM2) is frequently overexpressed in cancer cells.

Purpose of the Study:

• To investigate the mechanism by which PKM2 overexpression activates mTORC1 signaling in cancer.
• To identify PKM2 substrates and their role in mTORC1 regulation.
• To explore the therapeutic potential of targeting PKM2-mediated mTORC1 activation.

Main Methods:

• Quantitative phosphoproteomics to identify PKM2 substrates.
• Western blotting and immunoprecipitation to confirm protein interactions and phosphorylation.
• In vitro and in vivo cancer models to assess oncogenic growth and autophagy.
• Pharmacological inhibition using TEPP-46.

Main Results:

• PKM2 directly phosphorylates AKT1 substrate 1 (AKT1S1) at serine 202 and 203 (S202/203).
• PKM2-mediated AKT1S1 phosphorylation leads to mTORC1 activation independent of hormonal and nutrient signals.
• This activation accelerates tumor growth and inhibits autophagy in renal cell carcinoma (RCC) and breast cancer models.
• TEPP-46 treatment reversed these oncogenic effects by reducing S202/203 phosphorylation.

Conclusions:

• PKM2 overexpression drives constitutive mTORC1 activation in cancer through AKT1S1 phosphorylation.
• This pathway represents a novel mechanism of oncogenic signaling and a potential therapeutic target.
• PKM2 phosphorylome provides insights into cancer-specific signaling alterations.