Atlas of Genetics and Cytogenetics in Oncology and Haematology

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AKT1S1 (AKT1 substrate 1 (proline-rich)) Claudia Wiza, Emmani BM Nascimento, D Margriet Ouwens German Diabetes Centre, Institute for Clinical Biochemistry, 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)

Published in Atlas Database: November 2014 Online updated version : http://AtlasGeneticsOncology.org/Genes/AKT1S1ID44289ch19q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62494/11-2014-AKT1S1ID44289ch19q13.pdf DOI: 10.4267/2042/62494 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Akt1 substrate 1 (AKT1S1), also known as proline- Abstract rich Akt substrate of 40-kDa (PRAS40) is a component of the Akt and mammalian target of Review on AKT1S1, with data on DNA/RNA, on the rapamycin complex 1 (mTORC1) signaling cascades encoded and where the is implicated. (Nascimento and Ouwens, 2009; Wang et al., 2012; Keywords Wiza et al., 2012). AKT1S1 can act as a negative AKT1S1, cancer, type 2 diabetes regulator of the mTORC1 complex, and binds YWHAZ (14-3-3) when phosphorylated Identity (Nascimento and Ouwens, 2009; Wang et al., 2012; Wiza et al., 2012). Several tumors and tumor cell Other names lines display increased levels of phosphorylated Lobe AKT1S1 (Andersen et al., 2010; Huang and Porter, PRAS40 2005), but it is incompletely understood to what HGNC (Hugo) extent AKT1S1 participates in tumorigenesis. AKT1S1 Finally, AKT1S1 function is critical for the Location regulation of insulin sensitivity in skeletal muscle 19q13.33 (Wiza et al., 2014; Wiza et al., 2013a). Note

Figure 1. Genomic location of the AKT1S1 gene at 19.

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Figure 2. AKT1S1 transcript variants and isoforms.

undefined function. These are followed by two short DNA/RNA sequences, the TOS- and RAIP-motif that mediate Description the interaction with mTORC1 (Fonseca et al., 2007; Oshiro et al., 2007; Vander Haar et al., 2007; Wang The gene for AKT1S1 spans a genomic region of et al., 2007). The FVMDE-stretch (amino acids 149- 9324 bases, and is composed of seven exons. 153 of isoform A and amino acids 129-133 of Transcription isoform B) represents the TOS motif, while the KSLP-stretch (amino acids 202-205 of isoform A The gene encodes five transcript variants, which and 182-185 of isoform B) resembles the RAIP- result in two protein isoforms. The longest one, motif. Furthermore, the contain a leucine- transcript variant one, differs from the other variants enriched nuclear export sequence (amino acids 238- in the 5' untranslated region and results in the 276 247 of isoform A and amino acids 218-227 of amino acid protein isoform A. Transcript variants 2- isoform B) (Havel et al., 2014; Wiza et al., 2013b). 5 all result in the 256 amino acid protein isoform B. Finally, AKT1S1 is phosphorylated on multiple sites The gene for PRAS40 is ubiquitously expressed, but (Wiza et al., 2012) (Figure 3). While Akt, Pim-1 and there is no information on changes in the expression AGC-kinase have been linked to the phosphorylation of the various transcript variants among tissues and of Thr266/Thr246 (isoform A and B, respectively), organs. all other phosphorylations on AKT1S1 have been Protein ascribed to mTORC1 (Figure 3). Expression Note The protein shows a ubiquitous expression, but there The protein encoded by the AKT1S1 gene has been is no information available regarding the protein identified as YWHAZ (also known as 14-3-3) abundance of the two isoforms in various tissues and binding protein in lysates from PC12 cells treated organs. with epidermal growth factor or nerve growth factor, and was termed p39 (Harthill et al., 2002). This Localisation protein is identical to the YWHAZ-binding protein The protein is found both in the cytosol and in the 'proline-rich Akt-substrate of 40-kDa' purified from nucleus. The transport from the nucleus to the insulin-treated hepatoma cells (Kovacina et al., cytosol is mediated by the leucine-enriched nuclear 2003), and the nuclear phosphoprotein AKT1S1 export sequence at the carboxy terminus of the purified from HeLa cells (Beausoleil et al., 2004). protein (Havel et al., 2014; Wiza et al., 2013b). Furthermore, AKT1S1 is a component of the cytosolic mammalian target of rapamycin complex 1 Function (mTORC1) (Fonseca et al., 2007; Oshiro et al., 2007; Regulation of mTORC1 activity Sancak et al., 2007; Thedieck et al., 2007; Vander AKT1S1 acts as an inhibitor of mTORC1 activity Haar et al., 2007; Wang et al., 2007), and a nuclear (Wiza et al., 2012). Phosphorylation of AKT1S1 complex containing the ribosomal protein L11 results in the dissociation of the AKT1S1 from raptor (RPL11) (Havel et al., 2014). within the mTORC1 complex thereby promoting the activity of mTORC1 (Oshiro et al., 2007; Sancak et Description al., 2007; Vander Haar et al., 2007). However, The AKT1S1 proteins occur as two single knock-down of AKT1S1 impairs the polypeptide chain proteins of 276 (isoform A) and phosphorylation of mTORC1-substrates in certain 256 (isoform B) amino acids, respectively. Isoform cell types, suggesting that AKT1S1 is also important A differs from isoform B by a 20 amino acid for mTORC1 signaling via mechanisms which are extension at the amino terminus. Both isoforms share still incompletely understood (Fonseca et al., 2007; multiple conserved regions. At the amino terminus Hong-Brown et al., 2010; Wiza et al., 2013a). there are two proline-rich stretches with an as yet

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AKT1S1 (AKT1 substrate 1 (proline-rich)) Wiza C, et al.

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

Nucleolar stress response homologs for human AKT1S1 (Pallares-Cartes et al., Nuclear AKT1S1 binds to the ribosomal protein L11 2012; Sancak et al., 2007; Vander Haar et al., 2007). (RPL11) (Havel et al., 2014). This interaction is dependent on the phosphorylation of Ser221 and Mutations Thr246 within AKT1S1 (Havel et al., 2014). RPL11 has been linked to the inhibition of the E3 ubiquitin No specific mutations in AKT1S1 have been ligase HDM2. This results in increased p53 protein associated with pathological conditions. stability and activation of the nucleolar stress response pathway, which is defined as the activation Implicated in of a specific transcriptional program resulting in cell Various cancers cycle arrest, apoptosis or senescence. The activation of this pathway is prevented when RPL11 is bound Multiple cancers and cancer cell lines display to AKT1S1 (Havel et al., 2014). elevated levels of (phosphorylated) AKT1S1 (Huang Cell survival and Porter, 2005; Jiang et al., 2014). The elevated Akt1S1 protects neurons against cell death following levels of phosphorylated AKT1S1 are mostly found spinal cord injury (Saito et al., 2004). in associated with increased activity of kinases Overexpression of AKT1S1 in rats reduces infarct regulating the phosphorylation of AKT1S1, such as size following cerebral ischemia (Saito et al., 2006; Akt, Pim-1 and mTORC1. Nevertheless, some of the Yu et al., 2008). cellular functions of AKT1S1, such as the regulation Proteasome activity and insulin sensitivity of the nucleolar stress response, proteasome activity The silencing of AKT1S1 promotes the degradation and cell survival, suggest that AKT1S1 may of insulin receptor substrate 1 (IRS1) in skeletal participate in tumor progression. Finally, muscle through activation of the proteasome (Wiza pharmacological studies have identified et al., 2013a). As a consequence, the insulin- phosphorylated AKT1S1-Thr246 as suitable mediated activation of IRS1/Akt signaling pathway biomarker to predict the sensitivity to Akt-inhibitors regulating glucose uptake is impaired (Wiza et al., in multiple cancers (Andersen et al., 2010; 2013a). Conversely, overexpression of AKT1S1 Madhunapantula et al., 2011). inhibits proteasome activation and increases IRS1 Meningioma stability (Wiza et al., 2014). This results in increased Immunohistochemical examination of 25 WHO insulin sensitivity even under conditions of insulin grade I and 25 WHO grade II meningiomas showed resistance. Overexpression of AKT1S1 improves that 56% and 36% of the tumors were positive for insulin signaling via the IRS1/Akt-axis in the heart AKT1S1-Thr246 (Johnson et al., 2009). and liver of a high-fat diet mouse model for insulin resistance (Völkers et al., 2014). Melanoma Homology Phosphorylation of AKT1S1 was increased during melanoma tumor progression and closely related to AKT1S1 homologs in higher species are almost elevated Akt3 activity (Madhunapantula et al., identical to human AKT1S1 with conservation of the 2007). Knock-down of AKT1S1 decreased regulatory domains and phosphorylation sites. In anchorage-independent growth and increased lower species, like amphibians, fish, and insects, apoptosis in melanoma cell lines (Madhunapantula proteins almost identical to the carboxy terminus of et al., 2007). human AKT1S1 have been reported (Wiza et al., 2012). These proteins show conservation of the Non-small-cell lung cancer TOS- and RAIP-motif as well as of the key In radiation-resistant non-small cell lung cancer phosphorylation sites equivalent to Ser183 and cells, phosphorylation of AKT1S1 promotes the Thr246 of human AKT1S1. Importantly, in D. formation of a complex with YWHAZ and FOXO3, melanogaster, dPRAS40 is also a component of the and the translocation of this trimeric complex from dTORC1-complex, indicating that it is appropriate to the nucleus to the cytosol (Kim et al., 2011). This consider the variants found in these lower species as translocation prevents the induction of pro-apoptotic by FOXO3, such as Bim and FasL. Treatment

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with PIM-1 kinase inhibitors reduces the levels of factors and nutrients in rat PC12 pheochromocytoma cells. phosphorylated AKT1S1 thereby increasing the Biochem J. 2002 Dec 1;368(Pt 2):565-72 amount of nuclear FOXO3 and the radiation Havel JJ, Li Z, Cheng D, Peng J, Fu H. Nuclear PRAS40 sensitivity of the non-small cell lung cancer cells couples the Akt/mTORC1 signaling axis to the RPL11- HDM2-p53 nucleolar stress response pathway. Oncogene. (Kim et al., 2013; Kim et al., 2011). 2015 Mar 19;34(12):1487-98 Gastric cancer Hong-Brown LQ, Brown CR, Kazi AA, Huber DS, Pruznak Immunohistochemical examination of 114 gastric AM, Lang CH. Alcohol and PRAS40 knockdown decrease mTOR activity and protein synthesis via AMPK signaling cancer tumors showed that 45% of the tumors were and changes in mTORC1 interaction. J Cell Biochem. 2010 positive for phosphorylated AKT1S1-Thr246. Apr 15;109(6):1172-84 Furthermore, phosphorylated AKT1S1-Thr246 Huang B, Porter G. Expression of proline-rich Akt-substrate associated with malignant progression and poor PRAS40 in cell survival pathway and carcinogenesis. Acta prognosis of the patients (Lu et al., 2014). Pharmacol Sin. 2005 Oct;26(10):1253-8 Type 2 diabetes Jazet IM, Schaart G, Gastaldelli A, Ferrannini E, Hesselink MK, Schrauwen P, Romijn JA, Maassen JA, Pijl H, Ouwens The insulin-mediated phosphorylation of AKT1S1 DM, Meinders AE. Loss of 50% of excess weight using a on Ser183 and Thr246 in skeletal muscle is increased very low energy diet improves insulin-stimulated glucose after weight loss in obese patients with type 2 disposal and skeletal muscle insulin signalling in obese diabetes, indicating impaired phosphorylation of insulin-treated type 2 diabetic patients. Diabetologia. 2008 Feb;51(2):309-19 AKT1S1 in patients with type 2 diabetes (Jazet et al., 2008; Nascimento et al., 2010). Jiang N, Hjorth-Jensen K, Hekmat O, Iglesias-Gato D, Kruse T, Wang C, Wei W, Ke B, Yan B, Niu Y, Olsen JV, Diabetic nephropathy Flores-Morales A. In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant Glucose-induced phosphorylation of AKT1S1 on prostate cancer growth. Oncogene. 2015 May Thr246 associates with mesangial cell hypertrophy 21;34(21):2764-76 in a streptozotocin-induced rat model for type 1 Johnson MD, O'Connell M, Vito F, Bakos RS. Increased diabetes, and lipid droplet accumulation in human STAT-3 and synchronous activation of Raf-1-MEK-1- kidney cells (Dey et al., 2010; Hao et al., 2014). MAPK, and phosphatidylinositol 3-Kinase-Akt-mTOR pathways in atypical and anaplastic meningiomas. J Diabetic cardiomyopathy Neurooncol. 2009 Apr;92(2):129-36 Overexpression of AKT1S1 protects against the Kim W, Youn H, Kwon T, Kang J, Kim E, Son B, Yang HJ, development of diabetic cardiomyopathy in mice Jung Y, Youn B. PIM1 kinase inhibitors induce hearts by inhibition of hypertrophy and improved radiosensitization in non-small cell lung cancer cells. insulin signaling (Völkers et al., 2014). Pharmacol Res. 2013 Apr;70(1):90-101 Kovacina KS, Park GY, Bae SS, Guzzetta AW, Schaefer E, Birnbaum MJ, Roth RA. Identification of a proline-rich Akt References substrate as a 14-3-3 binding partner. J Biol Chem. 2003 Andersen JN, Sathyanarayanan S, Di Bacco A, Chi A, Mar 21;278(12):10189-94 Zhang T, Chen AH, Dolinski B, Kraus M, Roberts B, Arthur Lu YZ, Deng AM, Li LH, Liu GY, Wu GY. Prognostic role of W, Klinghoffer RA, Gargano D, Li L, Feldman I, et al.. phospho-PRAS40 (Thr246) expression in gastric cancer. Pathway-based identification of biomarkers for targeted Arch Med Sci. 2014 Feb 24;10(1):149-53 therapeutics: personalized oncology with PI3K pathway inhibitors. Sci Transl Med. 2010 Aug 4;2(43):43ra55 Madhunapantula SV, Mosca PJ, Robertson GP. The Akt signaling pathway: an emerging therapeutic target in Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, malignant melanoma. Cancer Biol Ther. 2011 Dec Villén J, Li J, Cohn MA, Cantley LC, Gygi SP. Large-scale 15;12(12):1032-49 characterization of HeLa cell nuclear phosphoproteins. Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12130-5 Nascimento EB, Snel M, Guigas B, van der Zon GC, Kriek J, Maassen JA, Jazet IM, Diamant M, Ouwens DM. Dey N, Ghosh-Choudhury N, Das F, Li X, Venkatesan B, Phosphorylation of PRAS40 on Thr246 by PKB/AKT Barnes JL, Kasinath BS, Ghosh Choudhury G. PRAS40 facilitates efficient phosphorylation of Ser183 by mTORC1. acts as a nodal regulator of high glucose-induced TORC1 Cell Signal. 2010 Jun;22(6):961-7 activation in glomerular mesangial cell hypertrophy. J Cell Physiol. 2010 Oct;225(1):27-41 Oshiro N, Takahashi R, Yoshino K, Tanimura K, Nakashima A, Eguchi S, Miyamoto T, Hara K, Takehana K, Avruch J, Fonseca BD, Smith EM, Lee VH, MacKintosh C, Proud CG. Kikkawa U, Yonezawa K. The proline-rich Akt substrate of PRAS40 is a target for mammalian target of rapamycin 40 kDa (PRAS40) is a physiological substrate of complex 1 and is required for signaling downstream of this mammalian target of rapamycin complex 1. J Biol Chem. complex. J Biol Chem. 2007 Aug 24;282(34):24514-24 2007 Jul 13;282(28):20329-39 Hao J, Li F, Liu W, Liu Q, Liu S, Li H, Duan H. Pallares-Cartes C, Cakan-Akdogan G, Teleman AA. Phosphorylation of PRAS40-Thr246 involved in renal lipid Tissue-specific coupling between insulin/IGF and TORC1 accumulation of diabetes. J Cell Physiol. 2014 signaling via PRAS40 in Drosophila. Dev Cell. 2012 Jan Aug;229(8):1069-77 17;22(1):172-82 Harthill JE, Pozuelo Rubio M, Milne FC, MacKintosh C. Saito A, Hayashi T, Okuno S, Nishi T, Chan PH. 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oxidative stress in mouse brains after transient focal Wang L, Harris TE, Roth RA, Lawrence JC Jr. PRAS40 cerebral ischemia. Stroke. 2006 Feb;37(2):513-7 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem. 2007 Jul Saito A, Narasimhan P, Hayashi T, Okuno S, Ferrand-Drake 6;282(27):20036-44 M, Chan PH. Neuroprotective role of a proline-rich Akt substrate in apoptotic neuronal cell death after stroke: Wiza C, Chadt A, Blumensatt M, Kanzleiter T, Herzfeld De relationships with nerve growth factor. J Neurosci. 2004 Feb Wiza D, Horrighs A, Mueller H, Nascimento EB, Schürmann 18;24(7):1584-93 A, Al-Hasani H, Ouwens DM. Over-expression of PRAS40 enhances insulin sensitivity in skeletal muscle. Arch Physiol Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang Biochem. 2014 May;120(2):64-72 SA, Spooner E, Carr SA, Sabatini DM. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Wiza C, Herzfeld de Wiza D, Nascimento EB, Lehr S, Al- Mol Cell. 2007 Mar 23;25(6):903-15 Hasani H, Ouwens DM. Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jenö P, in primary human skeletal muscle cells. Diabetologia. 2013 Arrieumerlou C, Hall MN. PRAS40 and PRR5-like protein May;56(5):1118-28 are new mTOR interactors that regulate apoptosis. PLoS One. 2007 Nov 21;2(11):e1217 Wiza C, Nascimento EB, Linssen MM, Carlotti F, Herzfeld de Wiza D, van der Zon GC, Maassen JA, Diamant M, Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Guigas B, Ouwens DM. Proline-rich Akt substrate of 40-kDa Insulin signalling to mTOR mediated by the Akt/PKB contains a nuclear export signal. Cell Signal. 2013 substrate PRAS40. Nat Cell Biol. 2007 Mar;9(3):316-23 Sep;25(9):1762-8 Völkers M, Doroudgar S, Nguyen N, Konstandin MH, Yu F, Narasimhan P, Saito A, Liu J, Chan PH. Increased Quijada P, Din S, Ornelas L, Thuerauf DJ, Gude N, Friedrich expression of a proline-rich Akt substrate (PRAS40) in K, Herzig S, Glembotski CC, Sussman MA. PRAS40 human copper/zinc-superoxide dismutase transgenic rats prevents development of diabetic cardiomyopathy and protects motor neurons from death after spinal cord injury. improves hepatic insulin sensitivity in obesity. EMBO Mol J Cereb Blood Flow Metab. 2008 Jan;28(1):44-52 Med. 2014 Jan;6(1):57-65 Wang H, Zhang Q, Wen Q, Zheng Y, Lazarovici P, Jiang H, This article should be referenced as such: Lin J, Zheng W. Proline-rich Akt substrate of 40kDa Wiza C, Nascimento EBM, Ouwens DM. AKT1S1 (AKT1 (PRAS40): a novel downstream target of PI3k/Akt substrate 1 (proline-rich)). Atlas Genet Cytogenet Oncol Haematol. 2015; 19(12):679-683. signaling pathway. Cell Signal. 2012 Jan;24(1):17-24

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