mTORC1 Signaling Can Regulate Growth Factor Activation of p44/42 Mitogen-activated Protein Kinases through Protein Phosphatase 2A

Abstract

. 1). The mTORC1 complex comprises mTOR, raptor, mLST8, PRAS40, and controls initiation of translation of ribosomal proteins and several proteins that regulate cell cycle. Activation of ribosomal S6K1 after mitogen stimulation is dependent on mTORC1 (2). Cap-dependent translation is facilitated by mTORC1's phosphorylation and inactivation of 4E-BP1, the suppressor of eukaryotic initiation factor 4E (3, 4). The emerging picture places mTORC1 in a central role in which it senses mitogenic stimuli and amino acid (5) nutrient (6) conditions or AMP levels (7,8) and coordinates many cellular processes related to growth and proliferation. Rapamycin, a macrocyclic lactone antibiotic, is a potent and highly selective inhibitor of mTORC1 (9).The mTORC2 complex (mTOR, rictor, mSIN1, and mLST8) is thought to control actin cytoskeleton organization and protein kinase C (reviewed in Refs. 9 -12). The mTORC2 complex also phosphorylates Akt(Ser 473 ), required for full activation (13) and negative regulation of FOXO1A (14). Activation of mTORC1 by insulin and insulin-like growth factors occurs through activation of phosphatidylinositol 3-kinase and Akt. Akt negatively regulates the tuberous sclerosis complex (TSC) composed of harmartin and tuberin that acts as a GTPase-activating protein to maintain Rheb in the GDP (inactive) form (15). Exactly how Rheb activates mTOR is unknown. The activity of TSC is regulated by hypoxia, increases in AMP that activate AMP-PK, a positive regulator of TSC activity, and by MAPKs p44/42 that phosphorylate and inactivate TSC, thus promoting mTORC1 activation (16 -20). Akt also phosphorylates and inactivates PRAS40, another negative regulator of mTOR (21).To date, there is no clear evidence of the exact mechanism by which mTORC1 controls growth-related cellular processes. In vitro, mTORC1 phosphorylates at least two residues (Thr 37 and Thr 46 ) of 22,23). Direct phosphorylation of S6K1 has also been reported (24). However, an alternative mechanism has been proposed in which mTOR kinase activity

Regulation of Karyopherin α1 and Nuclear Import by Mammalian Target of Rapamycin

“…In agreement, others have shown that mTORC1 can control the phosphorylation of downstream effectors (e.g. p70 S6 kinase, Erk) via PP2Ac (33)(34)(35). In fact, by immunoprecipitation, mTORC1 physically associated with KPNA1 in a complex that included its associated phosphatase PP2Ac.…”

Nerve Growth Factor Inhibits Na+/H+ Exchange and HCO3- Absorption through Parallel Phosphatidylinositol 3-Kinase-mTOR and ERK Pathways in Thick Ascending Limb

“…For example, ERK1/2 can induce p90 RSK -catalyzed phosphorylation and inactivation of TSC2, resulting in increased mTOR signaling and S6K activation independent of PI3K (46,56,57). Conversely, rapamycin has been shown to diminish growth factor-induced ERK activation in some cells, an effect that may involve mTOR modulating ERK phosphorylation through PP2A (55). Several findings suggest that these interactions are minimal or absent in the MTAL, at least with respect to NGFinduced inhibition of NHE1 and HCO 3 Ϫ absorption.…”

“…Future studies using cell systems that enable constitutive activation and/or knockdown of S6K will be required to establish directly a role for S6K in NHE1 regulation. Additional mTOR-associated proteins, such as protein phosphatase 2 (25,54,55), also could be involved in mTOR regulation of NHE1 activity.…”

Regulation of Protein Synthesis by Ionizing Radiation

“…8). Furthermore, mTOR activity was found to be required for maximal ERK activation following IR treatment (48), reported to be potentially mediated by mTOR regulation of protein phosphatase 2A activity on ERK (26). The lack of a pronounced biphasic translation response in highly transformed cells is likely the result of a largely constitutively active mTOR signaling pathway and increased basal ERK activity.…”