AKT1S1 (AKT1 substrate 1 (proline-rich))

2014-11-01   Claudia Wiza , Emmani BM Nascimento , D Margriet Ouwens 


Atlas Image
Figure 1. Genomic location of the AKT1S1 gene at chromosome 19.


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


Atlas Image
Figure 2. AKT1S1 transcript variants and isoforms.


The gene for AKT1S1 spans a genomic region of 9324 bases, and is composed of seven exons.


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.



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).


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).
Atlas Image
Figure 3. Primary structure of the AKT1S1 protein and phosphorylation sites. The amino acid numbering refers to protein isoform B.


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.


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).


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).


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).



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

Implicated in

Entity name
Various cancers
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 name
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 name
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 name
Non-small-cell lung cancer
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 name
Gastric cancer
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 name
Type 2 diabetes
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 name
Diabetic nephropathy
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 name
Diabetic cardiomyopathy
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).


Pubmed IDLast YearTitleAuthors
206861782010Pathway-based identification of biomarkers for targeted therapeutics: personalized oncology with PI3K pathway inhibitors.Andersen JN et al
153029352004Large-scale characterization of HeLa cell nuclear phosphoproteins.Beausoleil SA et al
206290862010PRAS40 acts as a nodal regulator of high glucose-induced TORC1 activation in glomerular mesangial cell hypertrophy.Dey N et al
176042712007PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex.Fonseca BD et al
243473882014Phosphorylation of PRAS40-Thr246 involved in renal lipid accumulation of diabetes.Hao J et al
122170782002Regulation of the 14-3-3-binding protein p39 by growth factors and nutrients in rat PC12 pheochromocytoma cells.Harthill JE et al
247048322015Nuclear PRAS40 couples the Akt/mTORC1 signaling axis to the RPL11-HDM2-p53 nucleolar stress response pathway.Havel JJ et al
201277212010Alcohol and PRAS40 knockdown decrease mTOR activity and protein synthesis via AMPK signaling and changes in mTORC1 interaction.Hong-Brown LQ et al
161744432005Expression of proline-rich Akt-substrate PRAS40 in cell survival pathway and carcinogenesis.Huang B et al
180801072008Loss of 50% of excess weight using a very low energy diet improves insulin-stimulated glucose disposal and skeletal muscle insulin signalling in obese insulin-treated type 2 diabetic patients.Jazet IM et al
250655962015In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth.Jiang N et al
190343852009Increased STAT-3 and synchronous activation of Raf-1-MEK-1-MAPK, and phosphatidylinositol 3-Kinase-Akt-mTOR pathways in atypical and anaplastic meningiomas.Johnson MD et al
233529802013PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells.Kim W et al
125244392003Identification of a proline-rich Akt substrate as a 14-3-3 binding partner.Kovacina KS et al
247012272014Prognostic role of phospho-PRAS40 (Thr246) expression in gastric cancer.Lu YZ et al
221571482011The Akt signaling pathway: an emerging therapeutic target in malignant melanoma.Madhunapantula SV et al
201389852010Phosphorylation of PRAS40 on Thr246 by PKB/AKT facilitates efficient phosphorylation of Ser183 by mTORC1.Nascimento EB et al
175178832007The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1.Oshiro N et al
222647322012Tissue-specific coupling between insulin/IGF and TORC1 signaling via PRAS40 in Drosophila.Pallares-Cartes C et al
163971812006Modulation of proline-rich akt substrate survival signaling pathways by oxidative stress in mouse brains after transient focal cerebral ischemia.Saito A et al
149732262004Neuroprotective role of a proline-rich Akt substrate in apoptotic neuronal cell death after stroke: relationships with nerve growth factor.Saito A et al
173862662007PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase.Sancak Y et al
180303482007PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis.Thedieck K et al
172777712007Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40.Vander Haar E et al
244089662014PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity.Völkers M et al
219066752012Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of PI3k/Akt signaling pathway.Wang H et al
175100572007PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding.Wang L et al
245760652014Over-expression of PRAS40 enhances insulin sensitivity in skeletal muscle.Wiza C et al
234600192013Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells.Wiza C et al
237120342013Proline-rich Akt substrate of 40-kDa contains a nuclear export signal.Wiza C et al
174573632008Increased expression of a proline-rich Akt substrate (PRAS40) in human copper/zinc-superoxide dismutase transgenic rats protects motor neurons from death after spinal cord injury.Yu F et al

Other Information

Locus ID:

NCBI: 84335
MIM: 610221
HGNC: 28426
Ensembl: ENSG00000204673


dbSNP: 84335
ClinVar: 84335
TCGA: ENSG00000204673


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Autophagy - animalKEGGko04140
mTOR signaling pathwayKEGGko04150
Autophagy - animalKEGGhsa04140
mTOR signaling pathwayKEGGhsa04150
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by AKT1 E17K in CancerREACTOMER-HSA-5674400
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
AKT phosphorylates targets in the cytosolREACTOMER-HSA-198323
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
PI3K CascadeREACTOMER-HSA-109704
PKB-mediated eventsREACTOMER-HSA-109703
mTOR signallingREACTOMER-HSA-165159
mTORC1-mediated signallingREACTOMER-HSA-166208
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by SCF-KITREACTOMER-HSA-1433557
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Cellular responses to stressREACTOMER-HSA-2262752
Cellular response to heat stressREACTOMER-HSA-3371556
HSF1-dependent transactivationREACTOMER-HSA-3371571
Longevity regulating pathwayKEGGhsa04211
Longevity regulating pathway - multiple speciesKEGGko04213
Longevity regulating pathway - multiple speciesKEGGhsa04213

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
173862662007PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase.500
172777712007Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40.454
175100572007PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding.177
176042712007PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex.105
183722482008Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation.74
292366922017Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40.56
223547852012Role of PRAS40 in Akt and mTOR signaling in health and disease.51
219066752012Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of PI3k/Akt signaling pathway.45
255313172015Transforming growth factor-β promotes prostate bone metastasis through induction of microRNA-96 and activation of the mTOR pathway.40
268761542016Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1.30


Claudia Wiza ; Emmani BM Nascimento ; D Margriet Ouwens

AKT1S1 (AKT1 substrate 1 (proline-rich))

Atlas Genet Cytogenet Oncol Haematol. 2014-11-01

Online version: http://atlasgeneticsoncology.org/gene/44289/akt1s1-(akt1-substrate-1-(proline-rich))