Dataset Information

Regulation of protein kinase C? Nuclear Import and Apoptosis by Mechanistic Target of Rapamycin Complex-1.

ABSTRACT: Inactivation of the protein complex 'mechanistic target of rapamycin complex 1' (mTORC1) can increase the nuclear content of transcriptional regulators of metabolism and apoptosis. Previous studies established that nuclear import of signal transducer and activator of transcription-1 (STAT1) requires the mTORC1-associated adaptor karyopherin-?1 (KPNA1) when mTORC1 activity is reduced. However, the role of other mTORC1-interacting proteins in the complex, including 'protein kinase C delta' (PKC?), have not been well characterized. In this study, we demonstrate that PKC?, a STAT1 kinase, contains a functional 'target of rapamycin signaling' (TOS) motif that directs its interaction with mTORC1. Depletion of KPNA1 by RNAi prevented the nuclear import of PKC? in cells exposed to the mTORC1 inhibitor rapamycin or amino acid restriction. Mutation of the TOS motif in PKC? led to its loss of regulation by mTORC1 or karyopherin-?1, resulting in increased constitutive nuclear content. In cells expressing wild-type PKC?, STAT1 activity and apoptosis were increased by rapamycin or interferon-?. Those expressing the PKC? TOS mutant exhibited increased STAT1 activity and apoptosis; further enhancement by rapamycin or interferon-?, however, was lost. Therefore, the TOS motif in PKC? is a novel structural mechanism by which mTORC1 prevents PKC? and STAT1 nuclear import, and apoptosis.

SUBMITTER: Layoun A

PROVIDER: S-EPMC6879585 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Regulation of protein kinase Cδ Nuclear Import and Apoptosis by Mechanistic Target of Rapamycin Complex-1.

Layoun Antonio A Goldberg Alexander A AA Baig Ayesha A Eng Mikaela M Attias Ortal O Nelson Kristoff K Carella Alexandra A Amberber Nahomi N Fielhaber Jill A JA Joung Kwang-Bo KB Schmeing T Martin TM Han Yingshan Y Downey Jeffrey J Divangahi Maziar M Roux Philippe P PP Kristof Arnold S AS

Scientific reports 20191126 1

Inactivation of the protein complex 'mechanistic target of rapamycin complex 1' (mTORC1) can increase the nuclear content of transcriptional regulators of metabolism and apoptosis. Previous studies established that nuclear import of signal transducer and activator of transcription-1 (STAT1) requires the mTORC1-associated adaptor karyopherin-α1 (KPNA1) when mTORC1 activity is reduced. However, the role of other mTORC1-interacting proteins in the complex, including 'protein kinase C delta' (PKCδ), ...[more]

PMID: 31772273

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Project description:OBJECTIVE:Temporal lobe epilepsy (TLE) is a chronic epilepsy syndrome defined by seizures and progressive neurological disabilities, including cognitive impairments, anxiety, and depression. Here, human TLE specimens were investigated focusing on the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and complex 2 (mTORC2) activities in the brain, given that both pathways may represent unique targets for treatment. METHODS:Surgically resected hippocampal and temporal lobe samples from therapy-resistant TLE patients were analyzed by western blotting to quantify the expression of established mTORC1 and mTORC2 activity markers and upstream or downstream signaling pathways involving the two complexes. Histological and immunohistochemical techniques were used to assess hippocampal and neocortical structural abnormalities and cell-specific expression of individual biomarkers. Samples from patients with focal cortical dysplasia (FCD) type II served as positive controls. RESULTS:We found significantly increased expression of phospho-mTOR (Ser2448), phospho-S6 (Ser235/236), phospho-S6 (Ser240/244), and phospho-Akt (Ser473) in TLE samples compared to controls, consistent with activation of both mTORC1 and mTORC2. Our work identified the phosphoinositide 3-kinase and Ras/extracellular signal-regulated kinase signaling pathways as potential mTORC1 and mTORC2 upstream activators. In addition, we found that overactive mTORC2 signaling was accompanied by induction of two protein kinase B-dependent prosurvival pathways, as evidenced by increased inhibitory phosphorylation of forkhead box class O3a (Ser253) and glycogen synthase kinase 3 beta (Ser9). INTERPRETATION:Our data demonstrate that mTOR signaling is significantly dysregulated in human TLE, offering new targets for pharmacological interventions. Specifically, clinically available drugs that suppress mTORC1 without compromising mTOR2 signaling, such as rapamycin and its analogs, may represent a new group of antiepileptogenic agents in TLE patients. Ann Neurol 2018;83:311-327.

Dataset Information

Regulation of protein kinase C? Nuclear Import and Apoptosis by Mechanistic Target of Rapamycin Complex-1.

Publications

Regulation of protein kinase Cδ Nuclear Import and Apoptosis by Mechanistic Target of Rapamycin Complex-1.

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