A positive role of mammalian Tip41-like protein, TIPRL, in the amino-acid dependent mTORC1-signaling pathway through interaction with PP2A

Abstract

Target of rapamycin complex 1 (TORC1) has a key role in cellular regulations in response to environmental conditions. In yeast, Tip41 downregulates TORC1 signaling via activation of PP2A phosphatase. We show here that overexpression of TIPRL, a mammalian Tip41, suppressed dephosphorylation of mechanistic TORC1 (mTORC1) substrates under amino acid withdrawal, and knockdown of TIPRL conversely attenuated phosphorylation of those substrates after amino acid refeeding. TIPRL associated with the catalytic subunit of PP2A (PP2Ac), which was required for the TIPRL action on mTORC1 signaling. Collectively, unlike yeast TIP41, TIPRL has a positive effect on mTORC1 signaling through the association with PP2Ac.

Keywords: 4E-BP1; Amino acid; HA; HCC; PP2A; PP2A catalytic subunit; PP2Ac; S6K1; TIPRL; TOR; TOR complex; TORC; TRAIL; Tap42; Tap42-interacting protein of 41kDa; Tip41; eIF4E-binding protein 1; hemagglutinin; hepatocellular carcinoma; mTOR; mTORC1; mechanistic TOR; p70 ribosomal protein S6 kinase 1; protein phosphatase 2A; siRNA; small interfering RNA; target of rapamycin; target of rapamycin signaling pathway regulator-like; tumor necrosis factor-related apoptosis-inducing ligand; type 2A phosphatase-associated protein of 42kDa.