Tyrosine phosphorylation of DEPTOR functions as a molecular switch to activate mTOR signaling

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Metabolic dysfunction drives tumorigenesis, with the mechanistic target of rapamycin (mTOR) pathway being a key regulator of cancer cell proliferation and survival.
• While the PI3K/AKT pathway often regulates mTOR, some cancers show mTOR activation without canonical pathway alterations, suggesting alternative regulatory mechanisms.
• DEPTOR, an endogenous inhibitor of mTOR, modulates both mTOR complexes, but its inhibitory function can be affected by post-translational modifications.

Purpose of the Study:

• To investigate post-translational modifications of DEPTOR that affect its inhibitory function on mTOR.
• To identify the specific kinase responsible for DEPTOR phosphorylation and its role in mTOR activation.
• To elucidate a novel regulatory mechanism for mTOR signaling in cancer.

Main Methods:

• Investigated the impact of DEPTOR post-translational modifications on mTOR interaction and activity.
• Utilized proximity biotinylation assays to identify kinases interacting with DEPTOR.
• Examined the role of spleen tyrosine kinase (SYK) in DEPTOR phosphorylation and its dependence on ephrin receptors.

Main Results:

• Phosphorylation of DEPTOR at tyrosine 289 was found to impair its binding to mTOR, leading to increased mTOR activation.
• Spleen tyrosine kinase (SYK) was identified as the kinase responsible for DEPTOR tyrosine 289 phosphorylation.
• This phosphorylation event was shown to be dependent on ephrin receptor signaling.

Conclusions:

• Phosphorylation of DEPTOR at tyrosine 289 acts as a novel molecular switch regulating both mTOR complex 1 and mTOR complex 2.
• This mechanism provides an alternative pathway for mTOR activation independent of canonical signaling, relevant to various cancers.
• The identification of SYK and ephrin receptors in this pathway opens new avenues for targeted cancer therapies.