AKT1S1

Summary

AKT1S1 (AKT1 substrate 1, HGNC:28426) is a protein-coding gene on chromosome 19q13.33, encoding Proline-rich AKT1 substrate 1 (Q96B36). 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.

AKT1S1 is a proline-rich substrate of AKT (MIM 164730) that binds 14-3-3 protein (see YWHAH, MIM 113508) when phosphorylated (Kovacina et al., 2003 [PubMed 12524439]).

Source: NCBI Gene 84335 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 80 total
• Druggable target: yes
• MANE Select transcript: NM_001098633

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28426
Approved symbol	AKT1S1
Name	AKT1 substrate 1
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	PRAS40, MGC2865, Lobe
Ensembl gene	ENSG00000204673
Ensembl biotype	protein_coding
OMIM	610221
Entrez	84335

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 27 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000344175, ENST00000391830, ENST00000391831, ENST00000391832, ENST00000391833, ENST00000391834, ENST00000391835, ENST00000482622, ENST00000599525, ENST00000867348, ENST00000867349, ENST00000867350, ENST00000867351, ENST00000867352, ENST00000867353, ENST00000867354, ENST00000867355, ENST00000867356, ENST00000867357, ENST00000867358, ENST00000867359, ENST00000913566, ENST00000913567, ENST00000913568, ENST00000913569, ENST00000913570, ENST00000913571, ENST00000913572

RefSeq mRNA: 5 — MANE Select: NM_001098633 NM_001098632, NM_001098633, NM_001278159, NM_001278160, NM_032375

CCDS: CCDS12784, CCDS59410

Canonical transcript exons

ENST00000344175 — 5 exons

Exon	Start	End
ENSE00000720573	49871547	49871716
ENSE00001191256	49871812	49871889
ENSE00001509838	49877237	49877355
ENSE00001930412	49869039	49870060
ENSE00003616139	49872917	49873302

Expression profiles

Bgee: expression breadth ubiquitous, 222 present calls, max score 95.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.1611 / max 238.1588, expressed in 1816 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182102	13.4726	1803
182100	12.8191	1784
182103	1.1825	830
182105	1.0301	329
182097	0.5585	332
182107	0.3939	199
182104	0.3826	162
182099	0.2677	91
182101	0.2298	74
182098	0.2182	87

Top tissues by expression

248 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	95.78	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.89	gold quality
muscle of leg	UBERON:0001383	94.83	gold quality
lower esophagus mucosa	UBERON:0035834	94.04	gold quality
right adrenal gland	UBERON:0001233	93.99	gold quality
right adrenal gland cortex	UBERON:0035827	93.82	gold quality
left adrenal gland	UBERON:0001234	93.63	gold quality
left adrenal gland cortex	UBERON:0035825	93.32	gold quality
mucosa of transverse colon	UBERON:0004991	93.24	gold quality
skin of leg	UBERON:0001511	93.05	gold quality
apex of heart	UBERON:0002098	92.93	gold quality
mucosa of stomach	UBERON:0001199	92.73	gold quality
right lobe of liver	UBERON:0001114	92.70	gold quality
skin of abdomen	UBERON:0001416	92.32	gold quality
adrenal cortex	UBERON:0001235	92.31	gold quality
lower esophagus	UBERON:0013473	92.23	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.23	gold quality
body of stomach	UBERON:0001161	91.98	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.97	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.80	gold quality
right coronary artery	UBERON:0001625	91.70	gold quality
heart left ventricle	UBERON:0002084	91.60	gold quality
esophagus	UBERON:0001043	91.54	gold quality
popliteal artery	UBERON:0002250	91.54	gold quality
tibial artery	UBERON:0007610	91.54	gold quality
esophagus mucosa	UBERON:0002469	91.50	gold quality
right atrium auricular region	UBERON:0006631	91.27	gold quality
adrenal gland	UBERON:0002369	91.18	gold quality
left coronary artery	UBERON:0001626	91.15	gold quality
aorta	UBERON:0000947	91.09	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.72
E-MTAB-7381	no	2954.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EWSR1

miRNA regulators (miRDB)

35 targeting AKT1S1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-3180	98.46	64.68	348
HSA-MIR-3180-3P	98.46	64.68	348
HSA-MIR-6816-5P	98.46	64.35	364
HSA-MIR-211-3P	98.14	66.77	1052
HSA-MIR-188-5P	97.89	67.01	756
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-6807-5P	97.51	64.25	1046

Literature-anchored findings (GeneRIF, showing 35)

• PRAS40 is an important regulator of insulin sensitivity of the Akt-mTOR pathway and a potential target for the treatment of cancers, insulin resistance and hamartoma syndromes. (PMID:17277771)
• PRAS40 inhibits cell growth, S6K1 phosphorylation, and rheb-induced activation of the mTORC1 pathway (PMID:17386266)
• PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. (PMID:17510057)
• PRAS40 acts downstream of mTORC1 but upstream of its effectors, such as S6K1 and 4E-BP1 (PMID:17604271)
• activation of mTORC1 signalling by phorbol esters does not require PRAS40 to be phosphorylated at Thr(246), bind to 14-3-3 or be released from mTORC1. (PMID:18215133)
• after mTORC1 kinase activation by upstream regulators, PRAS40 is phosphorylated directly by mTOR, thus contributing to the relief of PRAS40-mediated substrate competition. (PMID:18372248)
• phosphorylation of PRAS40 is critical for the activation of mTOR in CNI-induced VEGF overexpression and renal cancer progression. (PMID:21886838)
• PRAS40 is known for its ability to regulate the mammalian target of rapamycin complex 1 kinase activity, possessing a key regulatory role at the cross point of signal transduction pathways activated by growth factor receptors (PMID:21906675)
• PIM1-activated pPRAS40, AKT-activated pFOXO3a, and their complex formation with 14-3-3 could be key regulators of the radiation-induced radioresistance in NSCLC cells (PMID:21910584)
• dissociation of PRAS40 from insulin-stimulated 4E-BP protein binding to mTORC1 and enhanced mTORC1 substrate binding results from Akt and mTORC1 activation and makes little or no contribution to mTORC1 signaling (PMID:21914810)
• study found tuberin and PRAS40 to be potent anti-apoptotic gatekeepers in early stem-cell differentiation; data allow new insights into the regulation of early stem-cell maintenance and differentiation and identify a new role of the tumor suppressor tuberin and the oncogenic protein PRAS40 (PMID:22090422)
• our findings suggest that PRAS40 promotes the development of ESFT (PMID:22241085)
• This review summarizes the regulation and potential function(s) of PRAS40 in the complex Akt- and mTOR-signaling network in health and disease–{REVIEW} (PMID:22354785)
• WISP1 governs PRAS40 by sequestering PRAS40 intracellularly through post-translational phosphorylation. (PMID:22873724)
• Data suggest that PRAS40 modulates insulin action in skeletal muscle; knockdown of PRAS40 inhibits insulin action in cultured myotubes and is associated with up-regulation of IRS1 (insulin receptor substrate 1) degradation via proteasome proteolysis. (PMID:23460019)
• PRAS40 contains a functional nuclear export signal. Furthermore, enforced nuclear accumulation of PRAS40 impairs insulin action, thereby substantiating the function of this protein in the regulation of insulin sensitivity. (PMID:23712034)
• PRAS40 as a regulator of insulin sensitivity in hSkMC (PMID:24576065)
• Findings indicate that dual phosphorylation of PRAS40 by Akt and mTORC1 promotes formation of a nuclear-specific PRAS40- and RPL11-containing complex distinct from mTORC1 that inhibits the RPL11-HDM2-p53 pathway. (PMID:24704832)
• Supporting this idea, we identified a downstream target of the TGFb-miR-96 signaling pathway to be AKT1S1 mRNA, whose translated protein is a negative regulator of mTOR kinase. (PMID:25531317)
• The frameshift mutation detected in the current study would result in a premature stop of amino-acid synthesis in AKT1S1 protein and hence resembles a typical loss-of-function mutation. (PMID:25648575)
• This review discusses the role of PRAS40 and possible feedback mechanisms, and alterations in AKT/PRAS40/mTOR signaling that have been implicated in the pathogenesis of tumor progression. [review] (PMID:26003731)
• Phosphorylation of S202/203 of AKT1S1 by PKM2 released AKT1S1 from raptor and facilitated its binding to 14-3-3, resulted in hormonal- and nutrient-signals independent activation of mTORC1 signaling and led accelerated oncogenic growth and autophagy inhibition in cancer cells. (PMID:26876154)
• PRAS40 was downregulated in the DU145 cells following MYO6 knockdown. (PMID:27431378)
• The Akt-PRAS40 pathway is activated by uric acid, which inhibits autophagy and recapitulates the uric acid-induced proinflammatory cytokine phenotype. (PMID:28484006)
• Study found that activated PRAS40 acts not only as a regulator of TGFA-triggered exosome secretion but also as a common regulator of distinct microenvironmental and oncogenic signal-triggered exosome secretion in both normal and tumor cell types. PRAS40 is the first regulator identified for stress-induced exosome secretion. (PMID:28674187)
• crystal structures of RAPTOR-TOS motif complexes that define the determinants of TOS recognition, of an mTOR FKBP12-rapamycin-binding (FRB) domain-substrate complex that establishes a second substrate-recruitment mechanism, and of a truncated mTOR-PRAS40 complex that reveals PRAS40 inhibits both substrate-recruitment sites (PMID:29236692)
• ROS act in concert with BLM to facilitate Prostate cancer (PC) oncogenesis, potentially via further enhancing AKT signaling and downregulating PTEN expression. Importantly, inhibiting the BLM-AKT-PRAS40 axis induced PC cell apoptosis. (PMID:31210839)
• M2-polarized tumor-associated macrophages promote epithelial-mesenchymal transition via activation of the AKT3/PRAS40 signaling pathway in intrahepatic cholangiocarcinoma. (PMID:31692069)
• PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells. (PMID:31728028)
• This study, for the first time, links PF4’s anti-RNV function to an intracellular signaling molecule PRAS40 and its phosphorylation. (PMID:31740404)
• MELK is Upregulated in Advanced Clear Cell Renal Cell Carcinoma and Promotes Disease Progression by Phosphorylating PRAS40. (PMID:31813279)
• PRAS40 hyperexpression promotes hepatocarcinogenesis. (PMID:31901857)
• PRAS40 Phosphorylation Correlates with Insulin-Like Growth Factor-1 Receptor-Induced Resistance to Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer Cells. (PMID:32467173)
• Dual Specificity Kinase DYRK3 Promotes Aggressiveness of Glioblastoma by Altering Mitochondrial Morphology and Function. (PMID:33804169)
• PGK1 represses autophagy-mediated cell death to promote the proliferation of liver cancer cells by phosphorylating PRAS40. (PMID:35058442)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	akt1s1	ENSDARG00000074667
mus_musculus	Akt1s1	ENSMUSG00000011096
rattus_norvegicus	Akt1s1	ENSRNOG00000020289
drosophila_melanogaster	PRAS40	FBGN0267824

Protein

Protein identifiers

Proline-rich AKT1 substrate 1 — Q96B36 (reviewed: Q96B36)

Alternative names: 40 kDa proline-rich AKT substrate

All UniProt accessions (3): Q96B36, H9KV91, M0R2V8

UniProt curated annotations — full annotation on UniProt →

Function. 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. In absence of insulin and nutrients, AKT1S1 associates with the mTORC1 complex and directly inhibits mTORC1 activity by blocking the MTOR substrate-recruitment site. In response to insulin and nutrients, AKT1S1 dissociates from mTORC1. Its activity is dependent on its phosphorylation state and binding to 14-3-3. May also play a role in nerve growth factor-mediated neuroprotection.

Subunit / interactions. Associated component of the mechanistic target of rapamycin complex 1 (mTORC1), which contains core MTOR, MLST8 and RPTOR. Dissociates from mTORC1 in response to insulin treatment. mTORC1 binds to and is inhibited by FKBP12-rapamycin. Interacts (via TOS motif) with RPTOR; interaction is direct. The phosphorylated form interacts with 14-3-3 proteins.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed with highest levels of expression in liver and heart. Expressed at higher levels in cancer cell lines (e.g. A-549 and HeLa) than in normal cell lines (e.g. HEK293).

Post-translational modifications. Phosphorylated by AKT1; phosphorylation takes place in response to insulin treatment and promotes AKT1S1 interaction with 14-3-3 proteins, leading to relieve its inhibitor activity. Phosphorylated by MTOR following mTORC1 activation, inhibiting AKT1S1 inhibitor activity: phosphorylation by MTOR probably serves as a feedback loop that relieves inhibition from AKT1S1 in response to mTORC1 inactivation. Phosphorylation at Thr-246 by DYRK3 relieves inhibitory function on mTORC1.

Domain organisation. The TOS motif mediates interaction with RPTOR, leading to promote phosphorylation by mTORC1 complex.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96B36-1	1	yes
Q96B36-2	2
Q96B36-3	3

RefSeq proteins (5): NP_001092102, NP_001092103, NP_001265088, NP_001265089, NP_115751 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026682	AKT1S1	Family
IPR055192	PRAS_NT	Domain

Pfam: PF15798, PF22911

UniProt features (34 total): modified residue 11, mutagenesis site 7, region of interest 3, sequence conflict 3, compositionally biased region 3, splice variant 2, chain 1, sequence variant 1, strand 1, helix 1, short sequence motif 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5WBY	X-RAY DIFFRACTION	3.1
5WBL	X-RAY DIFFRACTION	3.35
5WBU	X-RAY DIFFRACTION	3.42
6SB0	ELECTRON MICROSCOPY	5.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96B36-F1	66.96	0.15

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (11): 92, 116, 183, 202, 203, 211, 212, 221, 246, 51, 88

Mutagenesis-validated functional residues (7):

Position	Phenotype
129	abolished association with the mtorc1 complex. does not affect phosphorylation by mtor.
183	reduced phosphorylation by mtor.
183	mimics phosphorylation; reduced interaction with rptor.
212	does not affect phosphorylation by mtor.
215–225	abolished ability to inhibit the kinase activity of mtor.
221	decreased interaction with 14-3-3; increased inhibitory activity toward mtorc1.
246	suppresses rps6kb1 phosphorylation by mtorc1.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-165159	MTOR signalling
R-HSA-166208	mTORC1-mediated signalling
R-HSA-198323	AKT phosphorylates targets in the cytosol
R-HSA-3371571	HSF1-dependent transactivation
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-2219528	PI3K/AKT Signaling in Cancer
R-HSA-2262752	Cellular responses to stress
R-HSA-3371556	Cellular response to heat stress
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9006925	Intracellular signaling by second messengers

MSigDB gene sets: 229 (showing top): CREL_01, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, FOXO1_01, GGAMTNNNNNTCCY_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, PATIL_LIVER_CANCER, PID_MTOR_4PATHWAY, GTGCCTT_MIR506, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, FREAC3_01, YY1_02, GOBP_NEGATIVE_REGULATION_OF_TOR_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS

GO Biological Process (12): negative regulation of protein kinase activity (GO:0006469), negative regulation of TOR signaling (GO:0032007), regulation of apoptotic process (GO:0042981), regulation of neuron apoptotic process (GO:0043523), negative regulation of cell size (GO:0045792), neurotrophin TRK receptor signaling pathway (GO:0048011), negative regulation of TORC1 signaling (GO:1904262), cytoplasmic translation (GO:0002181), cellular response to nutrient levels (GO:0031669), TORC1 signaling (GO:0038202), negative regulation of translational initiation (GO:0045947), positive regulation of translational initiation (GO:0045948)

GO Molecular Function (3): protein kinase inhibitor activity (GO:0004860), protein serine/threonine kinase inhibitor activity (GO:0030291), protein binding (GO:0005515)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), TORC1 complex (GO:0031931)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Signal Transduction	2
MTOR signalling	1
PIP3 activates AKT signaling	1
Cellular response to heat stress	1
PI3K/AKT Signaling in Cancer	1
Intracellular signaling by second messengers	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Cellular responses to stimuli	1
Cellular responses to stress	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein kinase activity	2
TOR signaling	2
translational initiation	2
regulation of translational initiation	2
negative regulation of protein phosphorylation	1
negative regulation of kinase activity	1
regulation of protein kinase activity	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
apoptotic process	1
regulation of programmed cell death	1
regulation of apoptotic process	1
neuron apoptotic process	1
regulation of cell size	1
cell surface receptor protein tyrosine kinase signaling pathway	1
neurotrophin signaling pathway	1
negative regulation of TOR signaling	1
TORC1 signaling	1
regulation of TORC1 signaling	1
translation	1
response to nutrient levels	1
cellular response to stimulus	1
negative regulation of translation	1
positive regulation of translation	1
kinase inhibitor activity	1
protein kinase regulator activity	1
protein serine/threonine kinase activity	1
protein kinase inhibitor activity	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
TOR complex	1

Protein interactions and networks

STRING

1762 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKT1S1	RPTOR	Q8N122	999
AKT1S1	DEPTOR	Q8TB45	998
AKT1S1	MLST8	Q9BVC4	998
AKT1S1	MTOR	P42345	997
AKT1S1	RICTOR	Q6R327	994
AKT1S1	TTI1	O43156	993
AKT1S1	FKBP8	Q14318	988
AKT1S1	RHEB	Q15382	980
AKT1S1	MAPKAP1	Q9BPZ7	967
AKT1S1	RPS6KB1	P23443	899
AKT1S1	AKT1	P31749	882
AKT1S1	PRR5	P85299	863
AKT1S1	TSC2	P49815	847
AKT1S1	FKBP1A	P20071	773
AKT1S1	EIF4EBP1	Q13541	762

IntAct

59 interactions, top by confidence:

A	B	Type	Score
RPTOR	MTOR	psi-mi:“MI:0914”(association)	0.980
MTOR	RICTOR	psi-mi:“MI:0914”(association)	0.970
YWHAH	TSC2	psi-mi:“MI:0914”(association)	0.850
AKT1S1	YWHAH	psi-mi:“MI:0914”(association)	0.840
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
AKT1S1	MTOR	psi-mi:“MI:0915”(physical association)	0.800
AKT1S1	MTOR	psi-mi:“MI:0914”(association)	0.800
YWHAB	AKT1S1	psi-mi:“MI:0914”(association)	0.790
RPTOR	AKT1S1	psi-mi:“MI:0407”(direct interaction)	0.770
YWHAB	WDR62	psi-mi:“MI:0914”(association)	0.770
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
YWHAZ	AKT1S1	psi-mi:“MI:0915”(physical association)	0.560
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAB	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
BMH1	AKT1S1	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
RAPTOR1	AKT1S1	psi-mi:“MI:0407”(direct interaction)	0.440
AKT1S1	RPS6KB1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
RPS6KA5	AKT1S1	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
ORF10	NUP42	psi-mi:“MI:0914”(association)	0.350

BioGRID (73): AKT1S1 (Affinity Capture-Western), AKT1S1 (Affinity Capture-Western), AKT1S1 (Biochemical Activity), AKT1S1 (Affinity Capture-Western), AKT1S1 (Affinity Capture-Western), AKT1S1 (Affinity Capture-Western), AKT1S1 (Affinity Capture-Western), AKT1S1 (Affinity Capture-MS), AKT1S1 (Affinity Capture-Western), YWHAZ (Affinity Capture-Western), AKT1S1 (Biochemical Activity), AKT1S1 (Affinity Capture-MS), AKT1S1 (FRET), AKT1S1 (Reconstituted Complex), AKT1S1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GUA5, A0A1B0GVQ0, A0A286YF18, A0JNN8, A2VDX9, A5PK62, A6NGB7, A9CBA0, O09800, P04488, P06480, P06764, P07646, P0C171, P0DJK0, P0DJK1, P0DMQ5, P13291, P22389, P36342, P46695, P98162, Q08102, Q1RMT9, Q2HJ59, Q3TYP4, Q5BIR3, Q5EAA5, Q5JTB6, Q5NRQ0, Q6F5E0, Q6VUC0, Q6VUP9, Q703F0, Q765Z5, Q867A9, Q867D0, Q89448, Q8MJW9, Q8TEF2

Diamond homologs: Q96B36, Q9D1F4

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
AKT2	down-regulates	AKT1S1	phosphorylation
MTOR	“down-regulates activity”	AKT1S1	phosphorylation
14-3-3	down-regulates	AKT1S1	binding
DYRK3	down-regulates	AKT1S1	phosphorylation
AKT1S1	“form complex”	mTORC1	binding
AKT	“down-regulates activity”	AKT1S1	phosphorylation
AKT2	“down-regulates activity”	AKT1S1	phosphorylation
AKT1	“down-regulates activity”	AKT1S1	phosphorylation
DYRK3	“down-regulates activity”	AKT1S1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	127.1×	1e-11
Activation of BAD and translocation to mitochondria	6	123.5×	4e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	108.9×	6e-10
Activation of BH3-only proteins	6	80.5×	4e-09
RHO GTPases activate PKNs	7	60.0×	9e-10
Intrinsic Pathway for Apoptosis	6	47.5×	8e-08
FOXO-mediated transcription	5	45.4×	2e-06
SARS-CoV-1-host interactions	7	33.2×	5e-08

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	45.8×	2e-05
intracellular protein localization	8	20.9×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

80 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1582 predictions. Top by Δscore:

Variant	Effect	Δscore
19:49870056:GAGGG:G	acceptor_gain	1.0000
19:49870058:GGGCT:G	acceptor_loss	1.0000
19:49870059:GG:G	acceptor_gain	1.0000
19:49870060:GCTGC:G	acceptor_loss	1.0000
19:49870061:C:CC	acceptor_gain	1.0000
19:49870061:CTGC:C	acceptor_loss	1.0000
19:49870062:T:A	acceptor_loss	1.0000
19:49871553:ATTCT:A	donor_gain	1.0000
19:49871557:T:A	donor_gain	1.0000
19:49871563:T:C	donor_gain	1.0000
19:49871714:CAT:C	acceptor_gain	1.0000
19:49871717:C:CC	acceptor_gain	1.0000
19:49878569:GAAG:G	donor_gain	1.0000
19:49878571:AGG:A	donor_loss	1.0000
19:49878573:GT:G	donor_loss	1.0000
19:49878574:T:G	donor_loss	1.0000
19:49870057:AGGG:A	acceptor_gain	0.9900
19:49870058:GGG:G	acceptor_gain	0.9900
19:49871712:GCCAT:G	acceptor_gain	0.9900
19:49871713:CCAT:C	acceptor_gain	0.9900
19:49871713:CCATC:C	acceptor_gain	0.9900
19:49871714:CATC:C	acceptor_gain	0.9900
19:49871715:ATC:A	acceptor_loss	0.9900
19:49871716:TC:T	acceptor_loss	0.9900
19:49871717:C:T	acceptor_loss	0.9900
19:49871718:T:G	acceptor_loss	0.9900
19:49871888:CC:C	acceptor_gain	0.9900
19:49871889:CC:C	acceptor_gain	0.9900
19:49871890:C:CA	acceptor_loss	0.9900
19:49871891:T:G	acceptor_loss	0.9900

AlphaMissense

1619 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:49869980:G:C	F236L	0.998
19:49869980:G:T	F236L	0.998
19:49869982:A:G	F236L	0.998
19:49870035:A:T	I218N	0.998
19:49869953:G:C	N245K	0.997
19:49869953:G:T	N245K	0.997
19:49869957:A:G	L244P	0.997
19:49869957:A:T	L244H	0.997
19:49870023:A:G	M222T	0.997
19:49870023:A:T	M222K	0.997
19:49870025:G:C	S221R	0.997
19:49870025:G:T	S221R	0.997
19:49870027:T:G	S221R	0.997
19:49870035:A:C	I218S	0.997
19:49871617:A:T	V186E	0.997
19:49870023:A:C	M222R	0.996
19:49870035:A:G	I218T	0.996
19:49871603:A:G	W191R	0.996
19:49871603:A:T	W191R	0.996
19:49871623:A:G	L184P	0.996
19:49871632:G:T	A181D	0.996
19:49871709:G:C	S155R	0.996
19:49871709:G:T	S155R	0.996
19:49871711:T:G	S155R	0.996
19:49871882:A:C	F129L	0.996
19:49871882:A:T	F129L	0.996
19:49871884:A:G	F129L	0.996
19:49873266:C:A	W10C	0.996
19:49873266:C:G	W10C	0.996
19:49869961:G:C	R243G	0.995

dbSNP variants (sampled 300 via entrez): RS1000002352 (19:49870494 G>A), RS1000415858 (19:49875615 C>A,T), RS1000625191 (19:49870530 C>T), RS1000990353 (19:49869608 CG>C), RS1001273441 (19:49869765 G>A,T), RS1001469063 (19:49879745 G>A,C), RS1001492452 (19:49874730 A>G), RS1001864543 (19:49869909 C>A,T), RS1001898725 (19:49869807 C>T), RS1001914913 (19:49877930 C>G,T), RS1001979388 (19:49875342 C>A,T), RS1002073449 (19:49874998 G>A,C), RS1002572311 (19:49873346 T>C), RS1002677734 (19:49873605 G>A,C), RS1002730449 (19:49878653 T>G)

Disease associations

OMIM: gene MIM:610221 | disease phenotypes: MIM:613722

GenCC curated gene-disease

Mondo (1): developmental and epileptic encephalopathy, 12 (MONDO:0013389)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1255161 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

29 measured of 64 human assays (64 total across all organisms); most potent 29 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-(1-(2,3-dihydro-1H-pyrrolo[2,3]pyrimidin-4-yl)piperazin-4-yl)-2-(4-(trifluoro-methyl)phenyl)ethanamine	IC50	62 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
{2-(4-Chlorophenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine	IC50	62 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
Dimethyl-[2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethyl-phenyl)-ethyl]-amine	IC50	62 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
2-[4-(5,6,7,8-Tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethyl-phenyl)-ethylamine	IC50	62 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
2-(4-Chloro-phenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethylamine	IC50	62 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
{2-(4-Chloro-3-fluoro-phenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine	IC50	62 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
{2-(3-Fluoro-4-trifluoromethyl-phenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine	IC50	62 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
2-(4-fluorophenyl)-2-[4-(7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-ethylamine	IC50	62 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
2-(4-Fluoro-phenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethylamine	IC50	62 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
2-(1-(5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethanamine	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
{2-(4-Chlorophenyl)-2-[4-(7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
[2-[4-(7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethyl]-dimethylamine	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
[2-[4-(6,7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethyl]-dimethylamine	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
{2-(4-Chlorophenyl)-2-[4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
2-[4-(7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethylamine	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
2-(4-Chlorophenyl)-2-[4-(7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-ethylamine	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
[2-[4-(7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-2-(3-fluoro-4-trifluoromethylphenyl)-ethyl]-dimethylamine	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
2-(4-Chloro-phenyl)-2-[4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethylamine	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
{2-(4-Chloro-3-fluoro-phenyl)-2-[4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
4-{4-[2-dimethylamino-1-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
4-{4-[2-dimethylamino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
4-(4-(1-(4-chloro-3-fluorophenyl)-2-(dimethylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
4-(4-(1-(4-chloro-3-fluorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one	IC50	300 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
2-[4-(6,7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-fluorophenyl)-ethylamine	IC50	750 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
[2-[4-(6,7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-dimethylamine	IC50	750 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
4-{4-[1-(4-chloro-phenyl)-2-(pyrrolidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one	IC50	750 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
4-{4-[1-(4-chloro-phenyl)-2-(piperidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one	IC50	750 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
4-{4-[1-(4-trifluoro-phenyl)-2-(piperidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one	IC50	750 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity
4-(4-(1-(4-chloro-3-fluorophenyl)-2-(piperidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one	IC50	750 nM	US-10287300: Heterocyclic derivatives as modulators of kinase activity

ChEMBL bioactivities

32 potent at pChembl≥5 of 32 total, top 32 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.21	IC50	62	nM	CHEMBL5877975
7.21	IC50	62	nM	CHEMBL5898630
7.21	IC50	62	nM	CHEMBL5986100
7.21	IC50	62	nM	CHEMBL5876997
7.21	IC50	62	nM	CHEMBL6024086
7.21	IC50	62	nM	CHEMBL6046384
7.21	IC50	62	nM	CHEMBL5955170
7.21	IC50	62	nM	CHEMBL5893996
7.21	IC50	62	nM	CHEMBL5832695
6.80	IC50	160	nM	CHEMBL1257282
6.52	IC50	300	nM	CHEMBL5979312
6.52	IC50	300	nM	CHEMBL5945590
6.52	IC50	300	nM	CHEMBL6011342
6.52	IC50	300	nM	CHEMBL5961208
6.52	IC50	300	nM	CHEMBL5946118
6.52	IC50	300	nM	CHEMBL6016163
6.52	IC50	300	nM	CHEMBL5897865
6.52	IC50	300	nM	CHEMBL6063949
6.52	IC50	300	nM	CHEMBL5933676
6.52	IC50	300	nM	CHEMBL5854309
6.52	IC50	300	nM	CHEMBL5902475
6.52	IC50	300	nM	CHEMBL5790050
6.52	IC50	300	nM	CHEMBL5849816
6.52	IC50	300	nM	CHEMBL5883619
6.12	IC50	750	nM	CHEMBL5822095
6.12	IC50	750	nM	CHEMBL5754362
6.12	IC50	750	nM	CHEMBL6015092
6.12	IC50	750	nM	CHEMBL5849010
6.12	IC50	750	nM	CHEMBL5762428
6.12	IC50	750	nM	CHEMBL5991040
5.82	IC50	1500	nM	CHEMBL1258330
5.38	IC50	4200	nM	CHEMBL1257283

PubChem BioAssay actives

3 with measured affinity, of 29 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R)-2-amino-3-(4-fluorophenyl)-1-[4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl]propan-1-one	516985: Inhibition of PRAS40 phosphorylation at Thr246 in human LNCaP cells after 1.5 hrs	ic50	0.1600	uM
(2R)-2-amino-3-(4-chlorophenyl)-1-(4-quinazolin-4-ylpiperazin-1-yl)propan-1-one	516985: Inhibition of PRAS40 phosphorylation at Thr246 in human LNCaP cells after 1.5 hrs	ic50	1.5000	uM
(2R)-2-amino-2-(2,3-dihydro-1H-inden-2-yl)-1-[4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl]ethanone	516985: Inhibition of PRAS40 phosphorylation at Thr246 in human LNCaP cells after 1.5 hrs	ic50	4.2000	uM

CTD chemical–gene interactions

64 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases phosphorylation, affects cotreatment, increases methylation, decreases expression	3
sodium arsenite	increases abundance, increases expression	2
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases phosphorylation	2
Resveratrol	decreases phosphorylation, affects cotreatment, decreases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation	2
aristolochic acid I	increases expression	1
GSK2110183	decreases phosphorylation	1
GSK2141795	decreases phosphorylation	1
AZD8186	affects phosphorylation	1
FR900359	affects phosphorylation	1
moringin	affects cotreatment, increases expression	1
mivebresib	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
titanium dioxide	decreases methylation	1
coumarin	affects phosphorylation	1
cupric oxide	increases phosphorylation	1
baohuoside I	decreases reaction, increases phosphorylation, decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
arctigenin	decreases phosphorylation, increases reaction	1
CGP 52608	affects binding, increases reaction	1
STO 609	affects cotreatment, decreases phosphorylation	1
ICG 001	decreases expression	1
abrine	increases expression	1
ON 01910	decreases phosphorylation	1
STA 9090	decreases phosphorylation	1
MK 2206	decreases phosphorylation, affects cotreatment	1
cabazitaxel	decreases expression	1
2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one	decreases phosphorylation	1
AZD4547	decreases phosphorylation	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1065067	Binding	Inhibition of PARS40 phosphorylation in human MDA-MB-361 cells by Western blotting	Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5’-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. — J Med Chem

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SC13	HAP1 AKT1S1 (-) 1	Cancer cell line	Male
CVCL_XL20	HAP1 AKT1S1 (-) 2	Cancer cell line	Male
CVCL_XL21	HAP1 AKT1S1 (-) 3	Cancer cell line	Male
CVCL_XL22	HAP1 AKT1S1 (-) 4	Cancer cell line	Male
CVCL_ZJ08	LanthaScreen PRAS40 HEK 293E	Transformed cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.