SIT1

Summary

SIT1 (signaling threshold regulating transmembrane adaptor 1, HGNC:17710) is a protein-coding gene on chromosome 9p13.3, encoding Signaling threshold-regulating transmembrane adapter 1 (Q9Y3P8). Negatively regulates TCR (T-cell antigen receptor)-mediated signaling in T-cells.

Enables kinase binding activity. Involved in regulation of T cell activation. Located in plasma membrane.

Source: NCBI Gene 27240 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 29 total
• MANE Select transcript: NM_014450

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17710
Approved symbol	SIT1
Name	signaling threshold regulating transmembrane adaptor 1
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	SIT
Ensembl gene	ENSG00000137078
Ensembl biotype	protein_coding
OMIM	604964
Entrez	27240

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000259608, ENST00000474403, ENST00000486859, ENST00000922878, ENST00000922879

RefSeq mRNA: 1 — MANE Select: NM_014450 NM_014450

CCDS: CCDS6582

Canonical transcript exons

ENST00000259608 — 5 exons

Exon	Start	End
ENSE00000928208	35649295	35650081
ENSE00000928211	35650502	35650637
ENSE00000928212	35650754	35650931
ENSE00003549496	35650184	35650245
ENSE00003592495	35650357	35650415

Expression profiles

Bgee: expression breadth ubiquitous, 154 present calls, max score 93.13.

FANTOM5 (CAGE): breadth broad, TPM avg 3.8278 / max 199.1499, expressed in 233 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100597	3.6522	156
100593	0.1465	79
100595	0.0159	10
100594	0.0131	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	93.13	gold quality
lymph node	UBERON:0000029	89.72	gold quality
blood	UBERON:0000178	87.16	gold quality
spleen	UBERON:0002106	87.04	gold quality
thymus	UBERON:0002370	86.94	gold quality
cervix squamous epithelium	UBERON:0006922	83.79	gold quality
vermiform appendix	UBERON:0001154	83.65	gold quality
caecum	UBERON:0001153	80.73	gold quality
superficial temporal artery	UBERON:0001614	76.91	silver quality
bone marrow cell	CL:0002092	75.34	gold quality
diaphragm	UBERON:0001103	74.85	gold quality
parotid gland	UBERON:0001831	74.52	gold quality
epithelium of nasopharynx	UBERON:0001951	73.94	silver quality
small intestine Peyer’s patch	UBERON:0003454	73.91	gold quality
bone marrow	UBERON:0002371	73.82	gold quality
tonsil	UBERON:0002372	72.99	gold quality
periodontal ligament	UBERON:0008266	72.50	gold quality
olfactory bulb	UBERON:0002264	71.81	gold quality
mucosa of transverse colon	UBERON:0004991	71.77	gold quality
type B pancreatic cell	CL:0000169	71.72	gold quality
small intestine	UBERON:0002108	71.55	gold quality
tongue squamous epithelium	UBERON:0006919	70.24	gold quality
ileal mucosa	UBERON:0000331	69.56	silver quality
trabecular bone tissue	UBERON:0002483	68.72	silver quality
leukocyte	CL:0000738	68.59	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	68.55	gold quality
squamous epithelium	UBERON:0006914	68.44	gold quality
gall bladder	UBERON:0002110	68.13	gold quality
vastus lateralis	UBERON:0001379	67.83	gold quality
gingival epithelium	UBERON:0001949	67.40	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-6505	yes	567.17
E-GEOD-70580	yes	221.33
E-CURD-112	yes	13.62
E-ANND-3	yes	5.95
E-CURD-88	no	3.66

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting SIT1, 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-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-6825-5P	99.96	69.81	3431
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-508-5P	99.41	64.25	1248
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-92A-1-5P	98.28	64.51	631
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-1914-5P	97.83	66.21	807
HSA-MIR-3928-3P	97.61	66.53	1096

Literature-anchored findings (GeneRIF, showing 2)

• SIT as an important modulator of TCR-mediated signaling that regulates T-cell activation, homeostasis and tolerance (PMID:21957439)
• SIT1 identifies circulating hypoactive T cells with elevated cytotoxic molecule secretion in systemic lupus erythematosus patients. (PMID:38691318)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sit1	ENSMUSG00000028460
rattus_norvegicus	Sit1	ENSRNOG00000021546

Protein

Protein identifiers

Signaling threshold-regulating transmembrane adapter 1 — Q9Y3P8 (reviewed: Q9Y3P8)

Alternative names: SHP2-interacting transmembrane adapter protein, Suppression-inducing transmembrane adapter 1, gp30/40

All UniProt accessions (1): Q9Y3P8

UniProt curated annotations — full annotation on UniProt →

Function. Negatively regulates TCR (T-cell antigen receptor)-mediated signaling in T-cells. Involved in positive selection of T-cells.

Subunit / interactions. Homodimer; disulfide-linked. When phosphorylated, interacts with PTPN11/SHP2, GRB2 and CSK.

Subcellular location. Cell membrane.

Tissue specificity. Specifically expressed in T- and B-cells. Present in plasma cells but not in germinal center B-cells (at protein level). Expressed in T- and B-cell lymphoma.

Post-translational modifications. Phosphorylated on tyrosines by LCK, FYN or ZAP70 upon TCR activation; which leads to the recruitment of PTPN11, GRB2 and CSK.

RefSeq proteins (1): NP_055265* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033269	Sit1	Family

UniProt features (28 total): modified residue 10, mutagenesis site 6, region of interest 5, topological domain 2, signal peptide 1, chain 1, glycosylation site 1, disulfide bond 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3P8-F1	61.19	0.09

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 (10): 80, 83, 90, 102, 127, 144, 148, 169, 182, 188

Disulfide bonds (1): 27

Glycosylation sites (1): 26

Mutagenesis-validated functional residues (6):

Position	Phenotype
26	abolishes glycosylation.
90	reduces interaction with grb2. abolishes interaction with grb2; when associated with f-188.
127	no effect on interaction with ptpn11 or grb2.
148	reduces interaction with ptpn11, no effect on inhibition of nf-at activation.
169	abolishes interaction with csk and impairs inhibition of nf-at activation.
188	reduces interaction with grb2. abolishes interaction with grb2; when associated with f-90.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 199 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, GOBP_T_CELL_HOMEOSTASIS, GOBP_LYMPHOCYTE_HOMEOSTASIS, MODULE_118, MODULE_379, GOMF_SH2_DOMAIN_BINDING, chr9p13, GOBP_ADAPTIVE_IMMUNE_RESPONSE, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, SABATES_COLORECTAL_ADENOMA_DN, MODULE_242, GOBP_REGULATION_OF_LYMPHOCYTE_ACTIVATION, GOBP_REGULATION_OF_T_CELL_ACTIVATION, SHEN_SMARCA2_TARGETS_DN

GO Biological Process (5): adaptive immune response (GO:0002250), signal transduction (GO:0007165), T cell homeostasis (GO:0043029), regulation of T cell activation (GO:0050863), immune system process (GO:0002376)

GO Molecular Function (3): kinase binding (GO:0019900), SH2 domain binding (GO:0042169), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), extracellular exosome (GO:0070062), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
immune response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
lymphocyte homeostasis	1
T cell activation	1
regulation of lymphocyte activation	1
biological_process	1
enzyme binding	1
protein domain specific binding	1
binding	1
membrane	1
cell periphery	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

384 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIT1	TRAT1	Q6PIZ9	589
SIT1	CD247	P20963	407
SIT1	ZAP70	P43403	401
SIT1	KIFAP3	Q92845	400
SIT1	LAX1	Q8IWV1	369
SIT1	FYN	P06241	350
SIT1	PLCG1	P19174	337
SIT1	FCRL2	Q96LA5	324
SIT1	LAT	O43561	316
SIT1	TMEM156	Q8N614	306
SIT1	LRRC24	Q50LG9	305
SIT1	PTPN6	P29350	304
SIT1	THEMIS	Q8N1K5	304
SIT1	F3	P13726	302
SIT1	CD7	P09564	265
SIT1	TIFA	Q96CG3	265

IntAct

32 interactions, top by confidence:

A	B	Type	Score
BMP10	SIT1	psi-mi:“MI:0915”(physical association)	0.560
PLN	SIT1	psi-mi:“MI:0915”(physical association)	0.560
APOL2	SIT1	psi-mi:“MI:0915”(physical association)	0.560
CLRN2	SIT1	psi-mi:“MI:0915”(physical association)	0.560
UPK1B	SIT1	psi-mi:“MI:0915”(physical association)	0.560
TSPAN33	SIT1	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	SIT1	psi-mi:“MI:0915”(physical association)	0.560
MALL	SIT1	psi-mi:“MI:0915”(physical association)	0.560
TMEM140	SIT1	psi-mi:“MI:0915”(physical association)	0.560
ITM2A	SIT1	psi-mi:“MI:0915”(physical association)	0.560
PTPN11	SIT1	psi-mi:“MI:0914”(association)	0.460
APOL2	SIT1	psi-mi:“MI:0915”(physical association)	0.000
CLRN2	SIT1	psi-mi:“MI:0915”(physical association)	0.000
UPK1B	SIT1	psi-mi:“MI:0915”(physical association)	0.000
TSPAN33	SIT1	psi-mi:“MI:0915”(physical association)	0.000
TMBIM6	SIT1	psi-mi:“MI:0915”(physical association)	0.000
PLN	SIT1	psi-mi:“MI:0915”(physical association)	0.000
MALL	SIT1	psi-mi:“MI:0915”(physical association)	0.000
TMEM140	SIT1	psi-mi:“MI:0915”(physical association)	0.000
ITM2A	SIT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): SIT1 (Synthetic Lethality), SIT1 (Affinity Capture-MS), SIT1 (Two-hybrid), SIT1 (Two-hybrid), SIT1 (Two-hybrid), TMBIM6 (Two-hybrid), MALL (Two-hybrid), TMEM140 (Two-hybrid), TSPAN33 (Two-hybrid), BMP10 (Two-hybrid), PLN (Two-hybrid), CLRN2 (Two-hybrid), SYK (Affinity Capture-Western), ZAP70 (Affinity Capture-Western), PTPN11 (Affinity Capture-Western)

ESM2 similar proteins: A0A1B0GW64, A0A5F4BST2, A0PJX4, A8MVS5, A8MWV9, B0FP48, E5RIL1, E9PGG2, O14836, O60320, O95998, P09564, Q01113, Q01114, Q13477, Q2KI80, Q2T9R2, Q3TS39, Q3UPR0, Q3URD2, Q4V9L6, Q5FVJ4, Q5M869, Q6A044, Q6UWJ8, Q75VT8, Q864V4, Q8BRJ3, Q8BX43, Q8C503, Q8IVY1, Q8K5A9, Q8N112, Q8NC24, Q8NDY8, Q8QZT4, Q8R138, Q969Z4, Q9BUF7, Q9CQM1

Diamond homologs: Q5M869, Q8C503, Q9Y3P8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

402 predictions. Top by Δscore:

Variant	Effect	Δscore
9:35650179:CTCA:C	donor_loss	1.0000
9:35650180:TCA:T	donor_loss	1.0000
9:35650181:CACCC:C	donor_loss	1.0000
9:35650182:A:AC	donor_gain	1.0000
9:35650182:AC:A	donor_gain	1.0000
9:35650182:ACC:A	donor_gain	1.0000
9:35650182:ACCCT:A	donor_loss	1.0000
9:35650183:C:CA	donor_gain	1.0000
9:35650183:C:CC	donor_gain	1.0000
9:35650183:CCC:C	donor_gain	1.0000
9:35650183:CCCT:C	donor_gain	1.0000
9:35650183:CCCTG:C	donor_gain	1.0000
9:35650241:CCGTC:C	acceptor_gain	1.0000
9:35650242:CGTC:C	acceptor_gain	1.0000
9:35650242:CGTCC:C	acceptor_gain	1.0000
9:35650243:GTC:G	acceptor_gain	1.0000
9:35650244:TC:T	acceptor_gain	1.0000
9:35650244:TCC:T	acceptor_loss	1.0000
9:35650245:CC:C	acceptor_gain	1.0000
9:35650246:C:CA	acceptor_loss	1.0000
9:35650246:C:CC	acceptor_gain	1.0000
9:35650252:C:CT	acceptor_gain	1.0000
9:35650253:G:T	acceptor_gain	1.0000
9:35650351:CCCTA:C	donor_loss	1.0000
9:35650352:CCTAC:C	donor_loss	1.0000
9:35650353:CTACC:C	donor_loss	1.0000
9:35650354:TACC:T	donor_loss	1.0000
9:35650356:CCTGT:C	donor_gain	1.0000
9:35650416:C:CC	acceptor_gain	1.0000
9:35650505:C:A	donor_gain	1.0000

AlphaMissense

1232 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:35649890:G:C	F183L	0.980
9:35649890:G:T	F183L	0.980
9:35649892:A:G	F183L	0.980
9:35649997:A:G	Y148H	0.966
9:35649996:T:C	Y148C	0.962
9:35649891:A:C	F183C	0.961
9:35649996:T:G	Y148S	0.949
9:35650052:G:C	S129R	0.948
9:35650052:G:T	S129R	0.948
9:35650054:T:G	S129R	0.948
9:35650605:A:G	W45R	0.948
9:35650605:A:T	W45R	0.948
9:35650381:C:A	G91W	0.943
9:35649869:G:C	N190K	0.941
9:35649869:G:T	N190K	0.941
9:35650376:G:C	N92K	0.939
9:35650376:G:T	N92K	0.939
9:35649930:G:T	A170D	0.936
9:35649997:A:C	Y148D	0.936
9:35650380:C:A	G91V	0.931
9:35650002:A:T	V146D	0.926
9:35649891:A:G	F183S	0.914
9:35650061:G:C	C126W	0.914
9:35649877:A:G	Y188H	0.909
9:35650063:A:G	C126R	0.904
9:35650380:C:T	G91E	0.904
9:35649873:G:T	A189D	0.901
9:35649928:A:G	S171P	0.901
9:35649997:A:T	Y148N	0.898
9:35650377:T:A	N92I	0.898

dbSNP variants (sampled 300 via entrez): RS1000652609 (9:35651432 T>C), RS1002229520 (9:35649451 A>G), RS1002981061 (9:35649408 G>A,T), RS1003340840 (9:35649613 G>A,C,T), RS1004159727 (9:35651830 A>T), RS1004407882 (9:35652146 G>A), RS1006246428 (9:35650747 A>G), RS1007526722 (9:35649889 G>A), RS1007797850 (9:35651302 C>T), RS1007896450 (9:35652906 T>C), RS1007927460 (9:35652574 A>G), RS1009403135 (9:35650811 T>A,G), RS1010615905 (9:35652663 C>T), RS1011750028 (9:35649643 A>T), RS1012921502 (9:35652059 C>A,T)

Disease associations

OMIM: gene MIM:604964 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

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: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	decreases expression, increases expression	2
ethyl-p-hydroxybenzoate	decreases expression	1
beta-lapachone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases expression	1
Caffeine	affects phosphorylation	1
Diuron	decreases expression	1
Lipopolysaccharides	decreases expression, affects cotreatment, decreases reaction	1
Urethane	decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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