AKT1S1

Last update 08 May 2025

Basic Info

Synonyms

40 kDa proline-rich AKT substrate, AKT1 substrate 1, AKT1S1

+ [4]

Introduction

Negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1), an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth (PubMed:17277771, PubMed:17386266, PubMed:17510057, PubMed:29236692). In absence of insulin and nutrients, AKT1S1 associates with the mTORC1 complex and directly inhibits mTORC1 activity by blocking the MTOR substrate-recruitment site (PubMed:29236692). In response to insulin and nutrients, AKT1S1 dissociates from mTORC1 (PubMed:17386266, PubMed:18372248). Its activity is dependent on its phosphorylation state and binding to 14-3-3 (PubMed:16174443, PubMed:18372248). May also play a role in nerve growth factor-mediated neuroprotection (By similarity).

100 Clinical Results associated with AKT1S1

100 Translational Medicine associated with AKT1S1

0 Patents (Medical) associated with AKT1S1

380

Literatures (Medical) associated with AKT1S1

01 Apr 2025·Anticancer Research

Fluoxetine Suppresses Osteosarcoma ProgressionIn Vivoby Inducing Apoptosis and Inhibiting the AKT/mTOR/NF-κB Signaling Pathway

Article

Author: Liu, Shih-Wei ; Li, Chi-Huan ; Chen, Yu-Hsi ; Hsu, Fei-Ting ; Ku, Ming-Chou

BACKGROUND/AIMOsteosarcoma (OSCC) remains a significant health concern, necessitating novel therapeutic strategies. This study investigated the anti-tumor effects of fluoxetine in an in vivo OSCC model.MATERIALS AND METHODSMice inoculated with U-2 OS cells were treated with fluoxetine (10 or 20 mg/kg) to evaluate tumor growth, metastasis, and underlying molecular mechanisms.RESULTSFluoxetine treatment resulted in a dose-dependent reduction in tumor volume and weight, without causing systemic toxicity, as confirmed by histopathological and biochemical analyses. Mechanistically, fluoxetine activated caspase-dependent apoptosis by up-regulating cleaved caspase-8, caspase-9, and caspase-3. It also inhibited OSCC metastasis by suppressing VEGF and MMP-9 expression, reducing epithelial-mesenchymal transition markers. Furthermore, fluoxetine significantly reduced the phosphorylation of AKT, PRAS40, mTOR, and NF-[Formula: see text]B, thereby disrupting key tumorigenic signaling pathways.CONCLUSIONFluoxetine demonstrates promising anti-tumor activity in OSCC by inducing apoptosis, inhibiting metastasis, and targeting oncogenic signaling pathways. These findings suggest that fluoxetine may serve as a potential therapeutic agent for OSCC, warranting further investigation for clinical application.

01 Dec 2024·Molecular Neurobiology

Role of PIM Kinase Inhibitor in the Treatment of Alzheimer’s Disease

Review

Author: Meur, Shreyasi ; Karati, Dipanjan ; Roy, Souvik ; Mukherjee, Swarupananda

Alzheimer's disease (AD), a neurodegenerative disorder, is the most prevalent form of senile dementia, causing progressive deterioration of cognition, behavior, and rational skills. Neuropathologically, AD is characterized by two hallmark proteinaceous aggregates: amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) formed of hyperphosphorylated tau. A significant study has been done to understand how Aβ and/or tau accumulation can alter signaling pathways that affect neuronal function. A conserved protein kinase known as the mammalian target of rapamycin (mTOR) is essential for maintaining the proper balance between protein synthesis and degradation. Overwhelming evidence shows mTOR signaling's primary role in age-dependent cognitive decline and the pathogenesis of AD. Postmortem human AD brains consistently show an upregulation of mTOR signaling. Confocal microscopy findings demonstrated a direct connection between mTOR and intraneuronal Aβ₄₂ through molecular processes of PRAS40 phosphorylation. By attaching to the mTORC1 complex, PRAS40 inhibits the activity of mTOR. Furthermore, inhibiting PRAS40 phosphorylation can stop the Aβ-mediated increase in mTOR activity, indicating that the accumulation of Aβ may aid in PRAS40 phosphorylation. Physiologically, PRAS40 is phosphorylated by PIM1 which is a serine/threonine kinase of proto-oncogene PIM kinase family. Pharmacological inhibition of PIM1 activity prevents the Aβ-induced mTOR hyperactivity in vivo by blocking PRAS40 phosphorylation and restores cognitive impairments by enhancing proteasome function. Recently identified small-molecule PIM1 inhibitors have been developed as potential therapeutic to reduce AD-neuropathology. This comprehensive study aims to address the activity of PIM1 inhibitor that has been tested for the treatment of AD, in addition to the pharmacological and structural aspects of PIM1.

01 Nov 2024·Phytomedicine

Leonurine improves atherosclerosis by activating foam cell autophagy and metabolic remodeling via METTL3-mediated AKT1S1 mRNA stability modulation

Article

Author: Yu, Xinyuan ; Wang, Xiaodan ; Yin, Kai ; Chen, Xu ; Zhu, Xiao ; Zhang, Yaoyuan ; Wang, Juan

BACKGROUNDAtherosclerosis (AS) is the most prevalent cardiovascular disease and remains the major contributor to death and mortality globally. Leonurine (LEO) is a unique alkaloid compound with protective effects on the cardiovascular system. However, the exact mechanisms underlying its cardiovascular-protecting action are still not fully elucidated. The methyltransferase 3 (METTL3), the catalytic core of the N6-methyladenosine modification (m⁶A) methyltransferase complex, has been shown to inhibit autophagy and exacerbate the process of AS via regulation of m⁶A modification of mRNA.PURPOSEWe aimed to determine whether the inhibited effect of LEO on AS is related to METTL3-mediated AKT1S1 stability.METHODSThe apolipoprotein E (ApoE) knockout mice was subjected to a high-fat diet (HFD), and THP-1 derived macrophages was exposed to oxidized low-density lipoprotein (ox-LDL), to establish the animal and cellular models of AS, respectively.RESULTSWe found that LEO effectively improved AS and reduced the plaque area and inflammation via diminishing macrophage lipid accumulation and remodeling the lipid metabolism profile. LEO activated ox-LDL-induced macrophage autophagy, enhancing lipid metabolism decrease, according to the lipidomic and molecular biology analyses. Additionally, LEO caused a marked increase in autophagy marker levels in mouse models with advanced AS. Furthermore, we found that LEO reactivated autophagy and reversed lipid accumulation by suppressing METTL3 expression. The m⁶A-seq from ox-LDL-induced macrophages showed that a total of five autophagy-related mRNA transcripts (AKT1S1, AKT1, RB1CC1, CFLAR, and MTMR4) were altered, and AKT1S1 was significantly upregulated by LEO. Mechanistically, LEO-mediated regulation of METTL3 decreased AKT1S1 expression by attenuating its mRNA stability. Silencing AKT1S1 inhibited LEO-METTL3 axis-mediated autophagy and enhanced lipid accumulation in ox-LDL-induced macrophages.CONCLUSIONThe study first revealed that LEO exerts anti-atherosclerotic effect by activating METTL3-mediated macrophage autophagy in vivo and in vitro. The mechanism of LEO was further found to be the enhancement of METTL3-mediated AKT1S1 stability to activate autophagy thereby reducing lipid accumulation. This study provides a new perspective of natural medicines on the treatment of AS via an epigenetic manner.

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AKT1S1

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