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Abstract

Abstract Review on AKT1S1, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

AKT1S1 (AKT1 substrate 1 (proline-rich))

Identity

Other namesLobe
PRAS40
HGNC (Hugo) AKT1S1
LocusID (NCBI) 84335
Atlas_Id 44289
Location 19q13.33
Location_base_pair Starts at 50372290 and ends at 50380644 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
  Figure 1. Genomic location of the AKT1S1 gene at chromosome 19.
Note Akt1 substrate 1 (AKT1S1), also known as proline-rich Akt substrate of 40-kDa (PRAS40) is a component of the Akt and mammalian target of rapamycin complex 1 (mTORC1) signaling cascades (Nascimento and Ouwens, 2009; Wang et al., 2012; Wiza et al., 2012). AKT1S1 can act as a negative regulator of the mTORC1 complex, and binds YWHAZ (14-3-3) when phosphorylated (Nascimento and Ouwens, 2009; Wang et al., 2012; Wiza et al., 2012). Several tumors and tumor cell lines display increased levels of phosphorylated AKT1S1 (Andersen et al., 2010; Huang and Porter, 2005), but it is incompletely understood to what extent AKT1S1 participates in tumorigenesis. Finally, AKT1S1 function is critical for the regulation of insulin sensitivity in skeletal muscle (Wiza et al., 2014; Wiza et al., 2013a).

DNA/RNA

 
  Figure 2. AKT1S1 transcript variants and isoforms.
Description The gene for AKT1S1 spans a genomic region of 9324 bases, and is composed of seven exons.
Transcription The gene encodes five transcript variants, which result in two protein isoforms. The longest one, transcript variant one, differs from the other variants in the 5' untranslated region and results in the 276 amino acid protein isoform A. Transcript variants 2-5 all result in the 256 amino acid protein isoform B. The gene for PRAS40 is ubiquitously expressed, but there is no information on changes in the expression of the various transcript variants among tissues and organs.

Protein

Note The protein encoded by the AKT1S1 gene has been identified as YWHAZ (also known as 14-3-3) binding protein in lysates from PC12 cells treated with epidermal growth factor or nerve growth factor, and was termed p39 (Harthill et al., 2002). This protein is identical to the YWHAZ-binding protein 'proline-rich Akt-substrate of 40-kDa' purified from insulin-treated hepatoma cells (Kovacina et al., 2003), and the nuclear phosphoprotein AKT1S1 purified from HeLa cells (Beausoleil et al., 2004). Furthermore, AKT1S1 is a component of the cytosolic mammalian target of rapamycin complex 1 (mTORC1) (Fonseca et al., 2007; Oshiro et al., 2007; Sancak et al., 2007; Thedieck et al., 2007; Vander Haar et al., 2007; Wang et al., 2007), and a nuclear complex containing the ribosomal protein L11 (RPL11) (Havel et al., 2014).
Description The AKT1S1 proteins occur as two single polypeptide chain proteins of 276 (isoform A) and 256 (isoform B) amino acids, respectively. Isoform A differs from isoform B by a 20 amino acid extension at the amino terminus. Both isoforms share multiple conserved regions. At the amino terminus there are two proline-rich stretches with an as yet undefined function. These are followed by two short sequences, the TOS- and RAIP-motif that mediate the interaction with mTORC1 (Fonseca et al., 2007; Oshiro et al., 2007; Vander Haar et al., 2007; Wang et al., 2007). The FVMDE-stretch (amino acids 149-153 of isoform A and amino acids 129-133 of isoform B) represents the TOS motif, while the KSLP-stretch (amino acids 202-205 of isoform A and 182-185 of isoform B) resembles the RAIP-motif. Furthermore, the proteins contain a leucine-enriched nuclear export sequence (amino acids 238-247 of isoform A and amino acids 218-227 of isoform B) (Havel et al., 2014; Wiza et al., 2013b). Finally, AKT1S1 is phosphorylated on multiple sites (Wiza et al., 2012) (Figure 3). While Akt, Pim-1 and AGC-kinase have been linked to the phosphorylation of Thr266/Thr246 (isoform A and B, respectively), all other phosphorylations on AKT1S1 have been ascribed to mTORC1 (Figure 3).
 
  Figure 3. Primary structure of the AKT1S1 protein and phosphorylation sites. The amino acid numbering refers to protein isoform B.
Expression The protein shows a ubiquitous expression, but there is no information available regarding the protein abundance of the two isoforms in various tissues and organs.
Localisation The protein is found both in the cytosol and in the nucleus. The transport from the nucleus to the cytosol is mediated by the leucine-enriched nuclear export sequence at the carboxy terminus of the protein (Havel et al., 2014; Wiza et al., 2013b).
Function Regulation of mTORC1 activity
AKT1S1 acts as an inhibitor of mTORC1 activity (Wiza et al., 2012). Phosphorylation of AKT1S1 results in the dissociation of the AKT1S1 from raptor within the mTORC1 complex thereby promoting the activity of mTORC1 (Oshiro et al., 2007; Sancak et al., 2007; Vander Haar et al., 2007). However, knock-down of AKT1S1 impairs the phosphorylation of mTORC1-substrates in certain cell types, suggesting that AKT1S1 is also important for mTORC1 signaling via mechanisms which are still incompletely understood (Fonseca et al., 2007; Hong-Brown et al., 2010; Wiza et al., 2013a).

Nucleolar stress response
Nuclear AKT1S1 binds to the ribosomal protein L11 (RPL11) (Havel et al., 2014). This interaction is dependent on the phosphorylation of Ser221 and Thr246 within AKT1S1 (Havel et al., 2014). RPL11 has been linked to the inhibition of the E3 ubiquitin ligase HDM2. This results in increased p53 protein stability and activation of the nucleolar stress response pathway, which is defined as the activation of a specific transcriptional program resulting in cell cycle arrest, apoptosis or senescence. The activation of this pathway is prevented when RPL11 is bound to AKT1S1 (Havel et al., 2014).

Cell survival
Akt1S1 protects neurons against cell death following spinal cord injury (Saito et al., 2004). Overexpression of AKT1S1 in rats reduces infarct size following cerebral ischemia (Saito et al., 2006; Yu et al., 2008).

Proteasome activity and insulin sensitivity
The silencing of AKT1S1 promotes the degradation of insulin receptor substrate 1 (IRS1) in skeletal muscle through activation of the proteasome (Wiza et al., 2013a). As a consequence, the insulin-mediated activation of IRS1/Akt signaling pathway regulating glucose uptake is impaired (Wiza et al., 2013a). Conversely, overexpression of AKT1S1 inhibits proteasome activation and increases IRS1 stability (Wiza et al., 2014). This results in increased insulin sensitivity even under conditions of insulin resistance. Overexpression of AKT1S1 improves insulin signaling via the IRS1/Akt-axis in the heart and liver of a high-fat diet mouse model for insulin resistance (Völkers et al., 2014).

Homology AKT1S1 homologs in higher species are almost identical to human AKT1S1 with conservation of the regulatory domains and phosphorylation sites. In lower species, like amphibians, fish, and insects, proteins almost identical to the carboxy terminus of human AKT1S1 have been reported (Wiza et al., 2012). These proteins show conservation of the TOS- and RAIP-motif as well as of the key phosphorylation sites equivalent to Ser183 and Thr246 of human AKT1S1. Importantly, in D. melanogaster, dPRAS40 is also a component of the dTORC1-complex, indicating that it is appropriate to consider the variants found in these lower species as homologs for human AKT1S1 (Pallares-Cartes et al., 2012; Sancak et al., 2007; Vander Haar et al., 2007).

Mutations

Note No specific mutations in AKT1S1 have been associated with pathological conditions.

Implicated in

Entity Various cancers
Note Multiple cancers and cancer cell lines display elevated levels of (phosphorylated) AKT1S1 (Huang and Porter, 2005; Jiang et al., 2014). The elevated levels of phosphorylated AKT1S1 are mostly found in associated with increased activity of kinases regulating the phosphorylation of AKT1S1, such as Akt, Pim-1 and mTORC1. Nevertheless, some of the cellular functions of AKT1S1, such as the regulation of the nucleolar stress response, proteasome activity and cell survival, suggest that AKT1S1 may participate in tumor progression. Finally, pharmacological studies have identified phosphorylated AKT1S1-Thr246 as suitable biomarker to predict the sensitivity to Akt-inhibitors in multiple cancers (Andersen et al., 2010; Madhunapantula et al., 2011).
  
Entity Meningioma
Note Immunohistochemical examination of 25 WHO grade I and 25 WHO grade II meningiomas showed that 56% and 36% of the tumors were positive for AKT1S1-Thr246 (Johnson et al., 2009).
  
Entity Melanoma
Note Phosphorylation of AKT1S1 was increased during melanoma tumor progression and closely related to elevated Akt3 activity (Madhunapantula et al., 2007). Knock-down of AKT1S1 decreased anchorage-independent growth and increased apoptosis in melanoma cell lines (Madhunapantula et al., 2007).
  
Entity Non-small-cell lung cancer
Note In radiation-resistant non-small cell lung cancer cells, phosphorylation of AKT1S1 promotes the formation of a complex with YWHAZ and FOXO3, and the translocation of this trimeric complex from the nucleus to the cytosol (Kim et al., 2011). This translocation prevents the induction of pro-apoptotic genes by FOXO3, such as Bim and FasL. Treatment with PIM-1 kinase inhibitors reduces the levels of phosphorylated AKT1S1 thereby increasing the amount of nuclear FOXO3 and the radiation sensitivity of the non-small cell lung cancer cells (Kim et al., 2013; Kim et al., 2011).
  
Entity Gastric cancer
Note Immunohistochemical examination of 114 gastric cancer tumors showed that 45% of the tumors were positive for phosphorylated AKT1S1-Thr246. Furthermore, phosphorylated AKT1S1-Thr246 associated with malignant progression and poor prognosis of the patients (Lu et al., 2014).
  
Entity Type 2 diabetes
Note The insulin-mediated phosphorylation of AKT1S1 on Ser183 and Thr246 in skeletal muscle is increased after weight loss in obese patients with type 2 diabetes, indicating impaired phosphorylation of AKT1S1 in patients with type 2 diabetes (Jazet et al., 2008; Nascimento et al., 2010).
  
Entity Diabetic nephropathy
Note Glucose-induced phosphorylation of AKT1S1 on Thr246 associates with mesangial cell hypertrophy in a streptozotocin-induced rat model for type 1 diabetes, and lipid droplet accumulation in human kidney cells (Dey et al., 2010; Hao et al., 2014).
  
Entity Diabetic cardiomyopathy
Note Overexpression of AKT1S1 protects against the development of diabetic cardiomyopathy in mice hearts by inhibition of hypertrophy and improved insulin signaling (Völkers et al., 2014).
  

External links

Nomenclature
HGNC (Hugo)AKT1S1   28426
Cards
AtlasAKT1S1ID44289ch19q13
Entrez_Gene (NCBI)AKT1S1  84335  AKT1 substrate 1 (proline-rich)
GeneCards (Weizmann)AKT1S1
Ensembl hg19 (Hinxton)ENSG00000204673 [Gene_View]  chr19:50372290-50380644 [Contig_View]  AKT1S1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000204673 [Gene_View]  chr19:50372290-50380644 [Contig_View]  AKT1S1 [Vega]
ICGC DataPortalENSG00000204673
TCGA cBioPortalAKT1S1
AceView (NCBI)AKT1S1
Genatlas (Paris)AKT1S1
WikiGenes84335
SOURCE (Princeton)AKT1S1
Genomic and cartography
GoldenPath hg19 (UCSC)AKT1S1  -     chr19:50372290-50380644 -  19q13.33   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)AKT1S1  -     19q13.33   [Description]    (hg38-Dec_2013)
EnsemblAKT1S1 - 19q13.33 [CytoView hg19]  AKT1S1 - 19q13.33 [CytoView hg38]
Mapping of homologs : NCBIAKT1S1 [Mapview hg19]  AKT1S1 [Mapview hg38]
OMIM610221   
Gene and transcription
Genbank (Entrez)AK055511 AK092610 AK123687 AK226004 AK316603
RefSeq transcript (Entrez)NM_001098632 NM_001098633 NM_001278159 NM_001278160 NM_032375
RefSeq genomic (Entrez)NC_000019 NC_018930 NT_011109 NW_004929415
Consensus coding sequences : CCDS (NCBI)AKT1S1
Cluster EST : UnigeneHs.610819 [ NCBI ]
CGAP (NCI)Hs.610819
Alternative Splicing : Fast-db (Paris)GSHG0033340
Alternative Splicing GalleryENSG00000204673
Gene ExpressionAKT1S1 [ NCBI-GEO ]     AKT1S1 [ SEEK ]   AKT1S1 [ MEM ]
SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ96B36 (Uniprot)
NextProtQ96B36  [Medical]
With graphics : InterProQ96B36
Splice isoforms : SwissVarQ96B36 (Swissvar)
Domains : Interpro (EBI)AKT1S1   
Related proteins : CluSTrQ96B36
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
DMDM Disease mutations84335
Blocks (Seattle)Q96B36
Human Protein AtlasENSG00000204673
Peptide AtlasQ96B36
HPRD12441
IPIIPI00549786   IPI00306195   IPI00853601   
Protein Interaction databases
DIP (DOE-UCLA)Q96B36
IntAct (EBI)Q96B36
FunCoupENSG00000204673
BioGRIDAKT1S1
IntegromeDBAKT1S1
STRING (EMBL)AKT1S1
Ontologies - Pathways
QuickGOQ96B36
Ontology : AmiGOprotein binding  nucleoplasm  cytoplasm  cytosol  cytosol  negative regulation of protein kinase activity  epidermal growth factor receptor signaling pathway  fibroblast growth factor receptor signaling pathway  TORC1 complex  negative regulation of TOR signaling  cellular response to heat  Fc-epsilon receptor signaling pathway  regulation of neuron apoptotic process  innate immune response  negative regulation of cell size  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  regulation of cellular response to heat  
Ontology : EGO-EBIprotein binding  nucleoplasm  cytoplasm  cytosol  cytosol  negative regulation of protein kinase activity  epidermal growth factor receptor signaling pathway  fibroblast growth factor receptor signaling pathway  TORC1 complex  negative regulation of TOR signaling  cellular response to heat  Fc-epsilon receptor signaling pathway  regulation of neuron apoptotic process  innate immune response  negative regulation of cell size  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  regulation of cellular response to heat  
Pathways : KEGGmTOR signaling pathway   
REACTOMEQ96B36 [protein]
REACTOME PathwaysREACT_116125 Disease [pathway]
REACTOME PathwaysREACT_6900 Immune System [pathway]
REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
Protein Interaction DatabaseAKT1S1
DoCM (Curated mutations)AKT1S1
Wikipedia pathwaysAKT1S1
Gene fusion - Rearrangements
Gene fusion: TCGA
Polymorphisms : SNP, variants
NCBI Variation ViewerAKT1S1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)AKT1S1
dbVarAKT1S1
ClinVarAKT1S1
1000_GenomesAKT1S1 
Exome Variant ServerAKT1S1
SNP (GeneSNP Utah)AKT1S1
SNP : HGBaseAKT1S1
Genetic variants : HAPMAPAKT1S1
Genomic Variants (DGV)AKT1S1 [DGVbeta]
Mutations
ICGC Data PortalAKT1S1 
TCGA Data PortalAKT1S1 
Tumor PortalAKT1S1
Somatic Mutations in Cancer : COSMICAKT1S1 
LOVD (Leiden Open Variation Database)genes/AKT1S1
LOVD (Leiden Open Variation Database)genes/AKT1S1
LOVD (Leiden Open Variation Database)genes/AKT1S1
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)19:50372290-50380644
CONAN: Copy Number AnalysisAKT1S1 
Mutations and Diseases : HGMDAKT1S1
OMIM610221   
MedgenAKT1S1
NextProtQ96B36 [Medical]
GENETestsAKT1S1
Disease Genetic AssociationAKT1S1
Huge Navigator AKT1S1 [HugePedia]  AKT1S1 [HugeCancerGEM]
snp3D : Map Gene to Disease84335
DGIdb (Drug Gene Interaction db)AKT1S1
BioCentury BCIQAKT1S1
General knowledge
Homologs : HomoloGeneAKT1S1
Homology/Alignments : Family Browser (UCSC)AKT1S1
Phylogenetic Trees/Animal Genes : TreeFamAKT1S1
Chemical/Protein Interactions : CTD84335
Chemical/Pharm GKB GenePA134943587
Clinical trialAKT1S1
Cancer Resource (Charite)ENSG00000204673
Other databases
Probes
Litterature
PubMed40 Pubmed reference(s) in Entrez
CoreMineAKT1S1
GoPubMedAKT1S1
iHOPAKT1S1

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Contributor(s)

Written11-2014Claudia Wiza, Emmani BM Nascimento, D Margriet Ouwens
German Diabetes Centre, Institute for Clinical Biochemistry and Pathobiochemistry, Duesseldorf, Germany (CW, DMO); German Centre for Diabetes Research (DZD e.V.), Partner Duesseldorf, Germany (CW, DMO); Department of Human Biology, Maastricht University Medical Center, Maastricht, The Netherlands (EBMN); Department of Endocrinology, Ghent University Hospital, Ghent, Belgium (DMO); Department of Internal Medicine, division 1, University Hospital Cologne, Cologne, Germany (CW)

Citation

This paper should be referenced as such :
Wiza C, Nascimento EBM, Ouwens DM
AKT1S1 (AKT1 substrate 1 (proline-rich));
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/AKT1S1ID44289ch19q13.html

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indexed on : Tue May 26 20:31:28 CEST 2015

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