Proline-rich AKT1 substrate 1 (AKT1S1)

The protein contains 256 amino acids for an estimated molecular weight of 27383 Da.

 

Subunit of mTORC1, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, AKT1S1 negatively regulates mTOR activity in a manner that is dependent on its phosphorylation state and binding to 14-3-3 proteins. Inhibits RHEB-GTP-dependent mTORC1 activation. Substrate for AKT1 phosphorylation, but can also be activated by AKT1-independent mechanisms. May also play a role in nerve growth factor-mediated neuroprotection. (updated: April 1, 2015)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  5. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete		TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.
Protein sequence (FASTA)
Protein coevolution profile (FreeContact)
Multiple Sequence Alignment (Muscle)

Interpro domains
Total structural coverage: 83%
Model score: 6
MODL_ROSETTA-3.4
MODL_MODELLER-9.18

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VariantDescription
dbSNP:rs17850191

The reference OMIM entry for this protein is 610221

Akt1 substrate 1, proline-rich; akt1s1
Proline-rich akt substrate, 40-kd; pras40
Mgc2865

DESCRIPTION

AKT1S1 is a proline-rich substrate of AKT (164730) that binds 14-3-3 protein (see YWHAH, 113508) when phosphorylated (Kovacina et al., 2003).

CLONING

Kovacina et al. (2003) isolated a novel Akt substrate and 14-3-3-binding protein, Akt1s1, which they called Pras40, from rat hepatoma cells. By EST database analysis, they identified mouse and human PRAS40. The deduced 256-amino acid human protein contains 2 N-terminal proline-rich regions and a C-terminal AKT phosphorylation site, thr246, that is conserved in rat and mouse. Northern blot analysis detected 2.6- and 1.8-kb PRAS40 transcripts in all tissues examined, with highest levels of both transcripts in liver and heart. EST database analysis suggested that these 2 transcripts are splice variants with identical coding regions.

GENE FUNCTION

By in vitro analysis of AKT phosphorylation of PRAS40 expressed in E. coli or HEK293 cells, Kovacina et al. (2003) confirmed that PRAS40 is a substrate for AKT phosphorylation. Additional transfection of HEK293 cells with a constitutively active form of AKT increased PRAS40 phosphorylation. Phosphorylation induced by constitutively active AKT was not blocked by a PI3K/AKT inhibitor, unlike that induced by wildtype AKT. Mutation analysis showed that phosphorylation of PRAS40 by AKT occurred at thr246. PRAS40 and 14-3-3 protein coimmunoprecipitated in transfected HEK293 cells. Far Western blot analysis showed that 14-3-3 bound endogenous PRAS40 in a prostate cancer cell line, and, using a reversible PI3K inhibitor, Kovacina et al. (2003) demonstrated that this binding was regulated by phosphorylation of PRAS40. Saito et al. (2004) showed that expression levels of phosphorylated mouse Pras40, phosphorylated Pras40 bound to phosphorylated Akt, and phosphorylated Pras40 bound to 14-3-3 protein all decreased in mouse brains after experimentally-induced transient focal cerebral ischemia (tFCI). Mouse brain cells overexpressing transfected human PRAS40 displayed decreased apoptotic neuronal cell death as measured by TUNEL analysis of DNA fragmentation. Saito et al. (2004) suggested that PRAS40 may play a role in NGF (162030)-mediated neuroprotection. Using immunoprecipitation analysis, Sancak et al. (2007) identified PRAS40 as a raptor (607130)-interacting protein that bound to MTOR (FRAP1; 601231) complex-1 (MTORC1) in insulin-deprived human embryonic kidney cells. PRAS40 inhibited cell growth, S6K1 (RPS6KB1; 608938) phosphorylation, and RHEB (601293)-induced activation of the MTORC1 pathway. In human embryonic kidney cells, it prevented the increase in MTORC1 kinase activity induced by RHEB-GTP. Insulin stimulated AKT-mediated phosphorylation of PRAS40, which prevented its inhibition of MTORC1.

MAPPING

The International Radiation Hybrid Mapping Consortium mapped the AKT1S1 gene to chromosome 19 (TMAP RH36488). ... More on the omim web site

Subscribe to this protein entry history

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

June 20, 2017: Protein entry updated
Automatic update: comparative model was added.

March 25, 2017: Additional information
No protein expression data in P. Mayeux work for AKT1S1

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 610221 was added.

Feb. 25, 2016: Protein entry updated
Automatic update: model status changed

Feb. 24, 2016: Protein entry updated
Automatic update: model status changed

Jan. 25, 2016: Protein entry updated
Automatic update: model status changed