CASTOR2

Summary

CASTOR2 (cytosolic arginine sensor for mTORC1 subunit 2, HGNC:37073) is a protein-coding gene on chromosome 7q11.23, encoding Cytosolic arginine sensor for mTORC1 subunit 2 (A6NHX0). Functions as a negative regulator of the TORC1 signaling pathway through the GATOR complex.

Enables identical protein binding activity. Involved in negative regulation of TORC1 signaling. Located in GATOR2 complex and cytosol.

Source: NCBI Gene 729438 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 4 total — 2 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_001145064

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:37073
Approved symbol	CASTOR2
Name	cytosolic arginine sensor for mTORC1 subunit 2
Location	7q11.23
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000274070
Ensembl biotype	protein_coding
OMIM	617033
Entrez	729438

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 retained_intron

ENST00000616305, ENST00000622472

RefSeq mRNA: 1 — MANE Select: NM_001145064 NM_001145064

CCDS: CCDS75620

Canonical transcript exons

ENST00000616305 — 9 exons

Exon	Start	End
ENSE00003719777	74964705	74965098
ENSE00003721638	75017990	75018122
ENSE00003725517	75007994	75008064
ENSE00003726745	75018972	75019095
ENSE00003728423	75024634	75031528
ENSE00003729992	75024440	75024534
ENSE00003744257	75021874	75021956
ENSE00003744695	75020039	75020149
ENSE00003751964	75017598	75017791

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 97.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.1072 / max 1291.8253, expressed in 1269 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79110	2.0072	536
79109	1.2245	718
204483	0.3897	196
204484	0.3416	166
204485	0.1441	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	97.63	gold quality
kidney epithelium	UBERON:0004819	96.39	silver quality
cardiac muscle of right atrium	UBERON:0003379	96.38	gold quality
vastus lateralis	UBERON:0001379	96.19	gold quality
quadriceps femoris	UBERON:0001377	96.16	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.14	gold quality
body of tongue	UBERON:0011876	96.13	gold quality
parotid gland	UBERON:0001831	96.06	gold quality
skeletal muscle tissue	UBERON:0001134	95.86	gold quality
substantia nigra pars compacta	UBERON:0001965	95.82	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.72	gold quality
lateral globus pallidus	UBERON:0002476	95.57	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.56	gold quality
deltoid	UBERON:0001476	94.98	gold quality
biceps brachii	UBERON:0001507	94.91	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.88	gold quality
pons	UBERON:0000988	94.74	gold quality
upper arm skin	UBERON:0004263	94.49	gold quality
pancreatic ductal cell	CL:0002079	94.43	silver quality
left ventricle myocardium	UBERON:0006566	94.43	gold quality
parietal lobe	UBERON:0001872	94.23	gold quality
postcentral gyrus	UBERON:0002581	94.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.71	gold quality
ventral tegmental area	UBERON:0002691	93.66	gold quality
entorhinal cortex	UBERON:0002728	93.58	gold quality
muscle tissue	UBERON:0002385	93.51	gold quality
dorsal plus ventral thalamus	UBERON:0001897	93.43	gold quality
subthalamic nucleus	UBERON:0001906	93.25	gold quality
superior vestibular nucleus	UBERON:0007227	93.24	gold quality
gastrocnemius	UBERON:0001388	93.14	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

336 targeting CASTOR2, 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-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882

Literature-anchored findings (GeneRIF, showing 1)

• Study establishes the CASTOR1 homodimer and CASTOR1-CASTOR2 heterodimer as arginine sensors for the mTORC1 pathway. (PMID:26972053)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	castor2	ENSDARG00000018985
mus_musculus	Castor2	ENSMUSG00000015944
rattus_norvegicus	Castor2	ENSRNOG00000067286

Paralogs (1): CASTOR1 (ENSG00000239282)

Protein

Protein identifiers

Cytosolic arginine sensor for mTORC1 subunit 2 — A6NHX0 (reviewed: A6NHX0)

Alternative names: Cellular arginine sensor for mTORC1 protein 2, GATS-like protein 2

All UniProt accessions (1): A6NHX0

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a negative regulator of the TORC1 signaling pathway through the GATOR complex. As part of homodimers or heterodimers with CASTOR1, directly binds and inhibits the GATOR subcomplex GATOR2 and thereby mTORC1. Does not directly bind arginine, but binding of arginine to CASTOR1 disrupts the interaction of CASTOR2-containing heterodimers with GATOR2 which can in turn activate mTORC1 and the TORC1 signaling pathway.

Subunit / interactions. Forms homodimers and heterodimers with CASTOR1. Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is not regulated by arginine.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed.

Similarity. Belongs to the GATS family.

RefSeq proteins (1): NP_001138536* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026249	CASTOR_fam	Family
IPR027795	CASTOR_ACT_dom	Domain
IPR040778	CASTOR1_N	Domain
IPR045865	ACT-like_dom_sf	Homologous_superfamily
IPR049479	CASTOR1_ACT-like	Domain
IPR051719	CASTOR_mTORC1	Family

Pfam: PF13840, PF18700, PF21389

UniProt features (3 total): domain 2, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9KPG	X-RAY DIFFRACTION	1.85
9KPB	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NHX0-F1	89.23	0.77

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-9639288	Amino acids regulate mTORC1
R-HSA-2262752	Cellular responses to stress
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711097	Cellular response to starvation

MSigDB gene sets: 128 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ACID_CHEMICAL, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM5, GOBP_NEGATIVE_REGULATION_OF_TOR_SIGNALING, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_TOR_SIGNALING, chr7q11, IVANOVA_HEMATOPOIESIS_STEM_CELL_LONG_TERM, DURCHDEWALD_SKIN_CARCINOGENESIS_DN

GO Biological Process (2): cellular response to L-arginine (GO:1903577), negative regulation of TORC1 signaling (GO:1904262)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (3): cytosol (GO:0005829), cytoplasm (GO:0005737), GATOR2 complex (GO:0061700)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cellular response to starvation	1
Cellular responses to stimuli	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cellular response to amino acid stimulus	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to L-arginine	1
negative regulation of TOR signaling	1
TORC1 signaling	1
regulation of TORC1 signaling	1
protein binding	1
binding	1
cytoplasm	1
intracellular anatomical structure	1
protein-containing complex	1
Seh1-associated complex	1

Protein interactions and networks

STRING

342 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASTOR2	WDR59	Q6PJI9	729
CASTOR2	WDR24	Q96S15	728
CASTOR2	SLC38A9	Q8NBW4	632
CASTOR2	MIOS	Q9NXC5	617
CASTOR2	SEH1L	Q96EE3	551
CASTOR2	SESN2	P58004	545
CASTOR2	GTF2I	P78347	540
CASTOR2	CASTOR1	Q8WTX7	530
CASTOR2	RRAGB	Q5VZM2	504
CASTOR2	KICS2	Q96MD2	504
CASTOR2	ITFG2	Q969R8	498
CASTOR2	SESN1	Q9Y6P5	498
CASTOR2	FAM72B	Q86X60	450
CASTOR2	KPTN	Q9Y664	448
CASTOR2	RRAGC	Q9HB90	446

IntAct

26 interactions, top by confidence:

A	B	Type	Score
CASTOR1	CASTOR2	psi-mi:“MI:0914”(association)	0.710
CASTOR1	CASTOR2	psi-mi:“MI:0915”(physical association)	0.710
CASTOR2	CASTOR1	psi-mi:“MI:0915”(physical association)	0.710
CASTOR2	MIOS	psi-mi:“MI:0915”(physical association)	0.500
CASTOR2	CASTOR2	psi-mi:“MI:0914”(association)	0.500
WDR59	CASTOR2	psi-mi:“MI:0914”(association)	0.500
CASTOR2	CASTOR2	psi-mi:“MI:0915”(physical association)	0.500
WDR59	CASTOR2	psi-mi:“MI:0915”(physical association)	0.500
WDR24	CASTOR2	psi-mi:“MI:0914”(association)	0.460
Sesn2	CASTOR2	psi-mi:“MI:0914”(association)	0.350
PLAAT4	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
RXRA	CASTOR2	psi-mi:“MI:0914”(association)	0.350

BioGRID (25): GATSL2 (Affinity Capture-MS), GATSL2 (Affinity Capture-MS), GATSL2 (Affinity Capture-Western), GATSL2 (Affinity Capture-Western), MIOS (Affinity Capture-Western), GATSL2 (Affinity Capture-Western), GATSL2 (Affinity Capture-Western), GATSL3 (Affinity Capture-Western), GATSL2 (Reconstituted Complex), GATSL3 (Reconstituted Complex), WDR24 (Affinity Capture-Western), GATSL2 (Affinity Capture-MS), GATSL2 (Proximity Label-MS), GATSL2 (Affinity Capture-MS), GATSL2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B4XBK1, A0A1B5L8S2, A0A1U8QK63, A0A3G9HHK2, A5ABG7, A6NHX0, A7SP74, B6JWC1, C5DLJ0, F4K0C4, I1R9A6, I1S489, K3UFY2, O13897, O14251, O22243, O74309, P0CI62, P46580, P9WEZ1, Q00868, Q09693, Q0D1P0, Q0V8A3, Q1EHT7, Q2QNU0, Q39469, Q44524, Q4WAZ4, Q5B7V0, Q5BJZ0, Q5R9D1, Q63ZZ8, Q6C5P9, Q6DDW7, Q753Y3, Q754C9, Q7SCC1, Q8CAB8, Q8TGA1

Diamond homologs: A6NHX0, Q0V8A3, Q5BJZ0, Q5R9D1, Q63ZZ8, Q6DDW7, Q8CAB8, Q8NAP1, Q8WTX7, Q9CWQ8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CASTOR2	“form complex”	“CASTOR1-CASTOR2 arginine binding complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
60247	GRCh38/hg38 7q11.23(chr7:74176025-75361855)x1	Pathogenic
687730	GRCh37/hg19 7q11.23(chr7:73799886-75388031)x1	Pathogenic
253341	GRCh37/hg19 7q11.23(chr7:73591993-75914797)x1	Likely pathogenic

SpliceAI

2581 predictions. Top by Δscore:

Variant	Effect	Δscore
7:74965036:T:A	donor_gain	1.0000
7:74965096:CAGGT:C	donor_loss	1.0000
7:74965097:C:CA	donor_loss	1.0000
7:74965098:A:AT	donor_loss	1.0000
7:74965099:G:C	donor_loss	1.0000
7:74965099:G:GG	donor_gain	1.0000
7:74965099:TA:T	donor_loss	1.0000
7:74965100:TTA:T	donor_loss	1.0000
7:74965101:CTTA:C	donor_loss	1.0000
7:75007978:C:CT	acceptor_gain	1.0000
7:75007979:T:TA	acceptor_gain	1.0000
7:75007983:A:AC	acceptor_gain	1.0000
7:75007983:A:C	acceptor_gain	1.0000
7:75007984:A:AG	acceptor_gain	1.0000
7:75007985:T:G	acceptor_gain	1.0000
7:75007987:A:AC	acceptor_gain	1.0000
7:75007987:A:C	acceptor_gain	1.0000
7:75007988:A:AG	acceptor_gain	1.0000
7:75007989:T:G	acceptor_gain	1.0000
7:75007990:T:G	acceptor_loss	1.0000
7:75007991:C:CC	acceptor_gain	1.0000
7:75007991:CAGGT:C	acceptor_loss	1.0000
7:75007991:CTGG:C	acceptor_loss	1.0000
7:75007992:A:AG	acceptor_gain	1.0000
7:75007992:A:C	acceptor_loss	1.0000
7:75007992:CCTGG:C	acceptor_loss	1.0000
7:75007993:G:GT	acceptor_gain	1.0000
7:75007993:GGT:G	acceptor_gain	1.0000
7:75007994:CAC:C	acceptor_gain	1.0000
7:75008061:CTAGG:C	donor_loss	1.0000

AlphaMissense

2159 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:74964993:T:C	L3P	1.000
7:74965014:T:C	L10P	1.000
7:75008001:T:C	F41L	1.000
7:75008002:T:C	F41S	1.000
7:75008003:C:A	F41L	1.000
7:75008003:C:G	F41L	1.000
7:75008007:A:C	S43R	1.000
7:75008009:T:A	S43R	1.000
7:75008009:T:G	S43R	1.000
7:75008011:T:C	L44P	1.000
7:75008035:C:T	T52I	1.000
7:75008044:T:A	V55D	1.000
7:75008055:G:A	G59R	1.000
7:75008055:G:C	G59R	1.000
7:75017639:T:A	W76R	1.000
7:75017639:T:C	W76R	1.000
7:75017641:G:C	W76C	1.000
7:75017641:G:T	W76C	1.000
7:75017646:C:A	A78D	1.000
7:75017649:T:C	L79P	1.000
7:75017709:T:A	I99N	1.000
7:75017709:T:G	I99S	1.000
7:75017712:C:A	A100D	1.000
7:75017721:T:A	V103D	1.000
7:75017724:T:A	I104N	1.000
7:75017733:T:A	L107Q	1.000
7:75017733:T:C	L107P	1.000
7:75017733:T:G	L107R	1.000
7:75017735:G:C	A108P	1.000
7:75017736:C:A	A108D	1.000

dbSNP variants (sampled 300 via entrez): RS1000195451 (7:75020905 A>G), RS1000303158 (7:75026008 C>G), RS1000374940 (7:75026343 C>T), RS1000609984 (7:75020740 C>T), RS1000639066 (7:75025007 C>T), RS1000646499 (7:75019932 C>T), RS1000713898 (7:75025218 G>A), RS1000935306 (7:75019744 G>A), RS1000978023 (7:75030062 C>G), RS1001205301 (7:75021794 T>G), RS1001307666 (7:75027240 G>A), RS1001325211 (7:75030284 G>A), RS1001380791 (7:75027427 T>C), RS1001599069 (7:75022066 G>T), RS1001920589 (7:75031543 G>T)

Disease associations

OMIM: gene MIM:617033 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002397_504	Mean spheric corpuscular volume	9.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	3
Air Pollutants	decreases expression, increases abundance	2
Estradiol	decreases expression, increases expression	2
triphenyl phosphate	affects expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
(+)-JQ1 compound	increases expression	1
Benzo(a)pyrene	increases methylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Urethane	increases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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