Mammalian target of rapamycin (mTOR) complex 2 regulates filamin A-dependent focal adhesion dynamics and cell...

Area of Science:

• Cellular Biology
• Molecular Signaling
• Biochemistry

Background:

• The mechanistic target of rapamycin (mTOR) pathway, comprising mTORC1 and mTORC2, regulates critical cellular functions.
• While mTORC1 is well-characterized, the signaling roles of mTORC2 remain less understood.
• Filamin A is an actin cross-linking protein involved in cellular structure and dynamics.

Purpose of the Study:

• To investigate the role of mTORC2 in the regulation of filamin A.
• To elucidate the functional consequences of mTORC2-mediated filamin A phosphorylation.

Main Methods:

• Phosphorylation analysis of filamin A at serine 2152 (S2152) using in vivo and cell-based assays.
• Treatment with mTORC1/mTORC2 inhibitor (Torin1) and mTORC1 inhibitor (rapamycin).
• Assessment of filamin A binding to β7-integrin, focal adhesion formation, and cell migration in filamin A-replete and deficient cells.

Main Results:

• mTORC2 was shown to phosphorylate filamin A at S2152.
• Torin1 treatment, but not rapamycin, reduced filamin A phosphorylation and its binding to β7-integrin.
• mTORC2 inhibition impaired focal adhesion formation and cell migration, effects rescued by wild-type filamin A but not a non-phosphorylatable mutant.

Conclusions:

• mTORC2 signaling directly regulates filamin A phosphorylation at S2152.
• This phosphorylation event is crucial for filamin A's role in focal adhesion assembly and cell migration.
• The findings reveal a novel mechanism by which mTORC2 controls cell motility through filamin A.