TIA1

Summary

TIA1 (TIA1 cytotoxic granule associated RNA binding protein, HGNC:11802) is a protein-coding gene on chromosome 2p13.3, encoding Cytotoxic granule associated RNA binding protein TIA1 (P31483). RNA-binding protein involved in the regulation of alternative pre-RNA splicing and mRNA translation by binding to uridine-rich (U-rich) RNA sequences.

The product encoded by this gene is a member of a RNA-binding protein family and possesses nucleolytic activity against cytotoxic lymphocyte (CTL) target cells. It has been suggested that this protein may be involved in the induction of apoptosis as it preferentially recognizes poly(A) homopolymers and induces DNA fragmentation in CTL targets. The major granule-associated species is a 15-kDa protein that is thought to be derived from the carboxyl terminus of the 40-kDa product by proteolytic processing. Alternative splicing resulting in different isoforms has been found for this gene.

Source: NCBI Gene 7072 — RefSeq curated summary.

At a glance

• Gene–disease (curated): distal myopathy, Welander type (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 360 total
• Phenotypes (HPO): 30
• Druggable target: yes
• MANE Select transcript: NM_022173

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11802
Approved symbol	TIA1
Name	TIA1 cytotoxic granule associated RNA binding protein
Location	2p13.3
Locus type	gene with protein product
Status	Approved
Aliases	TIA-1
Ensembl gene	ENSG00000116001
Ensembl biotype	protein_coding
OMIM	603518
Entrez	7072

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 15 protein_coding, 9 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000282574, ENST00000361692, ENST00000415783, ENST00000416149, ENST00000433529, ENST00000445587, ENST00000454815, ENST00000468787, ENST00000474699, ENST00000474809, ENST00000477044, ENST00000477415, ENST00000481650, ENST00000482876, ENST00000484065, ENST00000486392, ENST00000495774, ENST00000496096, ENST00000496452, ENST00000497672, ENST00000881358, ENST00000881359, ENST00000881360, ENST00000881361, ENST00000881362, ENST00000881363, ENST00000881364, ENST00000881365

RefSeq mRNA: 20 — MANE Select: NM_022173 NM_001351508, NM_001351509, NM_001351510, NM_001351511, NM_001351512, NM_001351513, NM_001351514, NM_001351515, NM_001351516, NM_001351517, NM_001351518, NM_001351519, NM_001351520, NM_001351521, NM_001351522, NM_001351523, NM_001351524, NM_001351525, NM_022037, NM_022173

CCDS: CCDS1900, CCDS1901, CCDS86846, CCDS86847, CCDS86848

Canonical transcript exons

ENST00000433529 — 13 exons

Exon	Start	End
ENSE00001698276	70209444	70212845
ENSE00001942458	70248405	70248628
ENSE00003458490	70224554	70224629
ENSE00003493099	70229059	70229091
ENSE00003493550	70216208	70216292
ENSE00003566761	70216886	70216994
ENSE00003604011	70215371	70215494
ENSE00003605947	70229264	70229318
ENSE00003627817	70230756	70230854
ENSE00003637040	70227735	70227822
ENSE00003642002	70236079	70236175
ENSE00003649765	70216404	70216499
ENSE00003663994	70214349	70214494

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.0663 / max 406.6553, expressed in 1778 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29020	36.5786	1822
29019	9.0440	1706
29021	3.0598	1447
29016	0.3238	153
29022	0.2740	123
29018	0.2077	89
29017	0.1571	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	99.06	gold quality
right ovary	UBERON:0002118	98.73	gold quality
ganglionic eminence	UBERON:0004023	98.71	gold quality
left ovary	UBERON:0002119	98.69	gold quality
adrenal tissue	UBERON:0018303	98.66	gold quality
ventricular zone	UBERON:0003053	98.63	gold quality
body of uterus	UBERON:0009853	98.47	gold quality
endocervix	UBERON:0000458	98.43	gold quality
rectum	UBERON:0001052	98.36	gold quality
body of pancreas	UBERON:0001150	98.32	gold quality
gall bladder	UBERON:0002110	98.24	gold quality
right lobe of thyroid gland	UBERON:0001119	98.09	gold quality
left lobe of thyroid gland	UBERON:0001120	98.02	gold quality
metanephros cortex	UBERON:0010533	97.94	gold quality
embryo	UBERON:0000922	97.91	gold quality
minor salivary gland	UBERON:0001830	97.82	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.77	gold quality
cortical plate	UBERON:0005343	97.76	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.72	gold quality
right adrenal gland cortex	UBERON:0035827	97.60	gold quality
stromal cell of endometrium	CL:0002255	97.59	gold quality
thyroid gland	UBERON:0002046	97.56	gold quality
ovary	UBERON:0000992	97.51	gold quality
left uterine tube	UBERON:0001303	97.46	gold quality
cerebellar hemisphere	UBERON:0002245	97.42	gold quality
right adrenal gland	UBERON:0001233	97.39	gold quality
ectocervix	UBERON:0012249	97.39	gold quality
adenohypophysis	UBERON:0002196	97.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.33	gold quality
transverse colon	UBERON:0001157	97.31	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

154 targeting TIA1, 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-4262	100.00	73.26	3931
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-493-5P	99.96	72.47	2382

Literature-anchored findings (GeneRIF, showing 40)

• apoptosis-promoting factor TIA-1 is a regulator of alternative pre-mRNA splicing (PMID:11106748)
• binding of TIA-1 in the vicinity of a 5’ ss helps to stabilize U1 snRNP recruitment, at least in part, via a direct interaction with U1-C (PMID:12486009)
• Data suggest that TIA-1 functions as a translational silencer of cyclooxygenase-2 (COX-2) expression and support the hypothesis that dysregulated RNA-binding of TIA-1 promotes COX-2 expression in neoplasia. (PMID:12885872)
• Increased TIA-1 gene expression is associated with sensitize endothelial cells to proapoptotic stimuli present in the tumor microenvironment and enhance NK cell cytotoxic activity against cancer cells in advanced soft tissue sarcoma (PMID:12949814)
• data indicate that, in CFTR exon 9, TIA-1 binding to the polypyrimidine-rich controlling element recruits U1 small nuclear ribonucleoprotein to the weak 5’-ss and induces exon inclusion (PMID:14966131)
• activated during HSV-1 infection and accumulated in cytoplasm of cells 6 hr after infection (PMID:15280467)
• TIA-1 represses the translation of target transcripts. (PMID:16227602)
• Results describe the gene expression of tristetraprolin, T-cell intracellular antigen and Hu antigen R in synovial tissues from rheumatoid arthritis and osteoarthritis patients. (PMID:16820934)
• FAST K synergizes with TIA-1/TIAR proteins to regulate Fas alternative splicing (PMID:17135269)
• TIAR regulates the relative expression of TIA-1 isoforms. (PMID:17488725)
• Cytotoxic molecule (CM) expression, specifically TIA1 and granzyme B, is predictive of prognosis in Hodgkin’s-like anaplastic large cell lymphoma. (PMID:17493234)
• dual role for TIA-1 in shuttling between DNA and RNA ligands to co-regulate COL2A1 expression at the level of transcription and pre-mRNA alternative splicing. (PMID:17580305)
• Positive correlations between TIA1 protein gene expression in patients with rheumatoid and healthy persons. (PMID:17599736)
• TIA-1-induced polysome disassembly is required for enhanced mRNA decay (PMID:17711853)
• Simultaneous knockdown of TIA1 and TIAL1 resulted in increased skipping of alternatively spliced exons associated with U-rich motifs, but did not affect alternatively spliced exons that are not associated with U-rich motifs. (PMID:18456862)
• Basophilic inclusions from patients with adult-onset atypical motor neuron disease were distinctly labeled with the antibodies against poly(A)-binding protein 1, T cell intracellular antigen 1, and ribosomal protein S6. (PMID:18642007)
• These data demonstrated that TIA-1 inhibits HBsAg expression by interacting with the posttranscriptional regulatory element (PRE) of hepatitis B virus. (PMID:18753794)
• Reults describe codependent functions of RSK2 and the apoptosis-promoting factor TIA-1 in stress granule assembly and cell survival. (PMID:18775331)
• TIA1 and TIAL1 regulate the alternate splicing of lysyl hydroxylase 2 (PMID:19110540)
• The carboxyl-terminal domain of TIA-1 is responsible for its recruitment into inclusions containing mutant huntingtin protein. (PMID:19386911)
• Sam68 is recruited into stress granules through complexing with TIA-1 in response to oxidative stress (PMID:19615357)
• Host immune responses to EOC vary widely according to histological subtype and the extent of residual disease. TIA-1, FoxP3 and CD20 emerge as new positive prognostic factors in high-grade serous EOC from optimally debulked patients (PMID:19641607)
• Down-regulation of the IGFBP-3 transcripts correlated with the up-regulation of the TIA-1 transcripts in primary HCC biopsies. (PMID:20599318)
• Data show that apoptotic (TIAR and TIA-1) marker expression in thyroid tissues from adolescents with immune thyroid diseases is higher than in non-immune thyroid diseases. (PMID:20675271)
• Severe hypoxia caused co-aggregation of TIAR/TIA-1 and these proteins suppressed HIF-1alpha expression. (PMID:20980400)
• Data show that TIA1 and TIAL1 bind at the same positions on human RNAs, and are consistent with a model where TIA proteins shorten the time available for definition of an alternative exon by enhancing recognition of the preceding 5’ splice site. (PMID:21048981)
• TIA-1 cytotoxic granule-associated RNA binding protein has a role in preventing progression of mismatch repair-proficient colorectal cancer (PMID:21179245)
• TIA1 and TIAR proteins are intron-associated positive regulators of SMN2 exon 7 splicing. (PMID:21189287)
• TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. (PMID:21257637)
• A role for TIA proteins as growth/tumour-suppressor genes. (PMID:21284605)
• Results characterise the C-terminal RRM2 and RRM3 domains of T-cell intracellular antigen-1 protein. (PMID:21846467)
• Three RNA recognition motifs participate in RNA recognition and structural organization by the pro-apoptotic factor TIA-1. (PMID:22154808)
• the TIA1 mutation causes perturbed RNA splicing and cellular stress resulting in WDM. (PMID:23348830)
• Welander distal myopathy is caused by mutated TIA1 through a dominant pathomechanism probably involving altered stress granule dynamics. (PMID:23401021)
• Work described here examined the punctate pattern of SRp20 localization in the cytoplasm of poliovirus-infected cells, demonstrating the partial co-localization of SRp20 with the stress granule marker protein TIA-1. (PMID:23830997)
• RNA binding mediated by either isolated RRM3 or the RRM23 construct is controlled by slight environmental pH changes due to the protonation/deprotonation of TIA-1 RRM3 histidine residues. (PMID:23902765)
• TIA1 gene expression do not predict prognosis in patients diagnosed with cutaneous T-cell lymphoma. (PMID:24433873)
• TIA1 inhibition of the exon 8 exclusion led to a decrease in SIRT1-Exon8 mRNA levels. (PMID:24566137)
• Structural insights into the role of binding avidity and the contributions of the TIA-1 RNA recognition motifs for recognition of pyrimidine-rich RNAs. (PMID:24682828)
• TIA proteins can function as long-term regulators of the ACTB mRNA metabolism in mouse and human cells. (PMID:24766723)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tia1l	ENSDARG00000026476
danio_rerio	tia1	ENSDARG00000052536
mus_musculus	Tia1	ENSMUSG00000071337
rattus_norvegicus	Tia1	ENSRNOG00000016813

Paralogs (36): DAZAP1 (ENSG00000071626), CIRBP (ENSG00000099622), RBM23 (ENSG00000100461), RBM3 (ENSG00000102317), NCL (ENSG00000115053), HNRNPA2B1 (ENSG00000122566), RBM19 (ENSG00000122965), RBM39 (ENSG00000131051), MSI1 (ENSG00000135097), HNRNPA1 (ENSG00000135486), HNRNPD (ENSG00000138668), HNRNPA1L2 (ENSG00000139675), RBMX (ENSG00000147274), A1CF (ENSG00000148584), TIAL1 (ENSG00000151923), RBM46 (ENSG00000151962), HNRNPDL (ENSG00000152795), MSI2 (ENSG00000153944), RBM47 (ENSG00000163694), RBMY1F (ENSG00000169800), HNRNPA3 (ENSG00000170144), RBMXL2 (ENSG00000170748), RBM4B (ENSG00000173914), RBM4 (ENSG00000173933), RBMXL3 (ENSG00000175718), HNRNPA0 (ENSG00000177733), TRNAU1AP (ENSG00000180098), HNRNPAB (ENSG00000197451), RBMXL1 (ENSG00000213516), HNRNPA1L3 (ENSG00000224578), RBMY1J (ENSG00000226941), RBMY1A1 (ENSG00000234414), RBMY1E (ENSG00000242389), RBMY1B (ENSG00000242875), RBMY1D (ENSG00000244395), DND1 (ENSG00000256453)

Protein

Protein identifiers

Cytotoxic granule associated RNA binding protein TIA1 — P31483 (reviewed: P31483)

Alternative names: Nucleolysin TIA-1 isoform p40, RNA-binding protein TIA-1, T-cell-restricted intracellular antigen-1, p40-TIA-1

All UniProt accessions (6): C9JTN7, E5RGV5, P31483, F8W8I6, F8WE16, H7BY49

UniProt curated annotations — full annotation on UniProt →

Function. RNA-binding protein involved in the regulation of alternative pre-RNA splicing and mRNA translation by binding to uridine-rich (U-rich) RNA sequences. Binds to U-rich sequences immediately downstream from a 5’ splice sites in a uridine-rich small nuclear ribonucleoprotein (U snRNP)-dependent fashion, thereby modulating alternative pre-RNA splicing. Preferably binds to the U-rich IAS1 sequence in a U1 snRNP-dependent manner; this binding is optimal if a 5’ splice site is adjacent to IAS1. Activates the use of heterologous 5’ splice sites; the activation depends on the intron sequence downstream from the 5’ splice site, with a preference for a downstream U-rich sequence. By interacting with SNRPC/U1-C, promotes recruitment and binding of spliceosomal U1 snRNP to 5’ splice sites followed by U-rich sequences, thereby facilitating atypical 5’ splice site recognition by U1 snRNP. Activates splicing of alternative exons with weak 5’ splice sites followed by a U-rich stretch on its own pre-mRNA and on TIAR mRNA. Acts as a modulator of alternative splicing for the apoptotic FAS receptor, thereby promoting apoptosis. Binds to the 5’ splice site region of FAS intron 5 to promote accumulation of transcripts that include exon 6 at the expense of transcripts in which exon 6 is skipped, thereby leading to the transcription of a membrane-bound apoptotic FAS receptor, which promotes apoptosis. Binds to a conserved AU-rich cis element in COL2A1 intron 2 and modulates alternative splicing of COL2A1 exon 2. Also binds to the equivalent AT-rich element in COL2A1 genomic DNA, and may thereby be involved in the regulation of transcription. Binds specifically to a polypyrimidine-rich controlling element (PCE) located between the weak 5’ splice site and the intronic splicing silencer of CFTR mRNA to promote exon 9 inclusion, thereby antagonizing PTB1 and its role in exon skipping of CFTR exon 9. Involved in the repression of mRNA translation by binding to AU-rich elements (AREs) located in mRNA 3’ untranslated regions (3’ UTRs), including target ARE-bearing mRNAs encoding TNF and PTGS2. Also participates in the cellular response to environmental stress, by acting downstream of the stress-induced phosphorylation of EIF2S1/EIF2A to promote the recruitment of untranslated mRNAs to cytoplasmic stress granules (SGs), leading to stress-induced translational arrest. Formation and recruitment to SGs is regulated by Zn(2+). Possesses nucleolytic activity against cytotoxic lymphocyte target cells. Displays enhanced splicing regulatory activity compared with TIA isoform Long.

Subunit / interactions. Homooligomer; homooligomerization is induced by Zn(2+). Interacts with FASTK; the interactions leads to its phosphorylation. Interacts (via RRM1 and the C-terminal glutamine-rich (Q) sequence) with SNRPC/U1-C (via N-terminus); thereby facilitating spliceosomal U1 snRNP recruitment to 5’ splice sites.

Subcellular location. Nucleus. Cytoplasm. Stress granule.

Tissue specificity. Expressed in heart, small intestine, kidney, liver, lung, skeletal muscle, testes, pancreas, and ovary (at protein level).

Post-translational modifications. Phosphorylated by FASTK; phosphorylation occurs after FAS ligation in FAS-mediated apoptosis and before DNA fragmentation.

Disease relevance. Welander distal myopathy (WDM) [MIM:604454] An autosomal dominant disorder characterized by adult onset of distal muscle weakness predominantly affecting the distal long extensors of the hands, with slow progression to involve all small hand muscles and the lower legs. Skeletal muscle biopsy shows myopathic changes and prominent rimmed vacuoles. Rare homozygous patients showed earlier onset, faster progression, and proximal muscle involvement. The disease is caused by variants affecting the gene represented in this entry. Amyotrophic lateral sclerosis 26, with or without frontotemporal dementia (ALS26) [MIM:619133] A form of amyotrophic lateral sclerosis, a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. ALS26 inheritance is autosomal dominant. Some patients may develop frontotemporal dementia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The RNA recognition motif domains RRM 2 and RRM 3 are necessary and sufficient for binding to uridine-rich target pre-mRNA. The RRM 1 and RRM 2 domains are required for the localization to stress granules (SGs) and for the recruitment of TIAR1 and poly(A) RNA to SGs in response to stress. The RRM2 domain and the C-terminal residues 287-340 contribute to nuclear localization. The RRM3 domain mediates nuclear export. The C-terminal glutamine-rich (Q) sequence in combination with the RRM 1 domain is required for the interaction with SNRPC/U1-C and to facilitate recruitment of spliceosomal U1 snRNP to 5’ splice sites.

Isoforms (3)

UniProt ID	Names	Canonical?
P31483-1	Long, a	yes
P31483-2	Short, b
P31483-3	3

RefSeq proteins (20): NP_001338437, NP_001338438, NP_001338439, NP_001338440, NP_001338441, NP_001338442, NP_001338443, NP_001338444, NP_001338445, NP_001338446, NP_001338447, NP_001338448, NP_001338449, NP_001338450, NP_001338451, NP_001338452, NP_001338453, NP_001338454, NP_071320, NP_071505* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR003954	RRM_euk-type	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034496	TIAR_RRM3	Domain
IPR034827	TIA-1_RRM1	Domain
IPR034830	TIA1_RRM2	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily

Pfam: PF00076

UniProt features (45 total): strand 15, helix 9, sequence variant 7, domain 3, turn 3, splice variant 3, chain 1, sequence conflict 1, region of interest 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
7VI4	ELECTRON CRYSTALLOGRAPHY	0.95
7VI5	ELECTRON CRYSTALLOGRAPHY	1.76
3BS9	X-RAY DIFFRACTION	1.95
5ITH	X-RAY DIFFRACTION	2.31
6ELD	X-RAY DIFFRACTION	2.48
5O3J	X-RAY DIFFRACTION	2.97
9KTZ	ELECTRON MICROSCOPY	3.1
9KTY	ELECTRON MICROSCOPY	3.36
2MJN	SOLUTION NMR
5O2V	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31483-F1	73.65	0.47

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 (1): 1

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6803529	FGFR2 alternative splicing
R-HSA-162582	Signal Transduction
R-HSA-190236	Signaling by FGFR
R-HSA-5654738	Signaling by FGFR2
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 314 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, TGCGCANK_UNKNOWN, PAL_PRMT5_TARGETS_UP, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, REACTOME_SIGNALING_BY_FGFR, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, KYNG_DNA_DAMAGE_DN, DARWICHE_PAPILLOMA_PROGRESSION_RISK, BILD_SRC_ONCOGENIC_SIGNATURE, YY1_Q6, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, GOBP_TRANSLATION, BILD_HRAS_ONCOGENIC_SIGNATURE, PAX8_B

GO Biological Process (10): regulation of alternative mRNA splicing, via spliceosome (GO:0000381), negative regulation of cytokine production (GO:0001818), mRNA processing (GO:0006397), apoptotic process (GO:0006915), RNA splicing (GO:0008380), negative regulation of translation (GO:0017148), stress granule assembly (GO:0034063), regulation of mRNA splicing, via spliceosome (GO:0048024), protein localization to cytoplasmic stress granule (GO:1903608), positive regulation of epithelial cell apoptotic process (GO:1904037)

GO Molecular Function (7): RNA binding (GO:0003723), mRNA 3’-UTR binding (GO:0003730), poly(A) binding (GO:0008143), mRNA 3’-UTR AU-rich region binding (GO:0035925), nucleic acid binding (GO:0003676), mRNA binding (GO:0003729), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), nuclear stress granule (GO:0097165), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by FGFR2	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by FGFR	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
negative regulation of gene expression	2
RNA processing	2
binding	2
alternative mRNA splicing, via spliceosome	1
regulation of mRNA splicing, via spliceosome	1
cytokine production	1
regulation of cytokine production	1
negative regulation of multicellular organismal process	1
mRNA metabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
translation	1
regulation of translation	1
negative regulation of protein metabolic process	1
membraneless organelle assembly	1
mRNA splicing, via spliceosome	1
regulation of RNA splicing	1
regulation of mRNA processing	1
protein localization to organelle	1
positive regulation of apoptotic process	1
epithelial cell apoptotic process	1
regulation of epithelial cell apoptotic process	1
nucleic acid binding	1
mRNA binding	1
poly-purine tract binding	1
mRNA 3’-UTR binding	1
RNA binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
cytoplasmic ribonucleoprotein granule	1
nuclear ribonucleoprotein granule	1
protein-containing complex	1

Protein interactions and networks

STRING

3236 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIA1	G3BP1	Q13283	997
TIA1	TIAL1	Q01085	982
TIA1	ELAVL1	Q15717	968
TIA1	EIF4G1	Q04637	962
TIA1	SNRPC	P09234	953
TIA1	EIF4E	P06730	934
TIA1	PABPC1	P11940	920
TIA1	TARDBP	Q13148	904
TIA1	RPS6KA3	P51812	887
TIA1	ATXN2	Q99700	887
TIA1	EIF3B	P55884	874
TIA1	PCBP2	Q15366	867
TIA1	ZFP36	P26651	854
TIA1	FUS	P35637	836
TIA1	CAPRIN1	Q14444	836

IntAct

93 interactions, top by confidence:

A	B	Type	Score
SNRPC	TIA1	psi-mi:“MI:0915”(physical association)	0.600
SNRPC	TIA1	psi-mi:“MI:0407”(direct interaction)	0.600
STT3A	RPN1	psi-mi:“MI:0914”(association)	0.560
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530
SNRPA	TIA1	psi-mi:“MI:0915”(physical association)	0.520
PARK7	TIA1	psi-mi:“MI:0915”(physical association)	0.460
PARK7	TIA1	psi-mi:“MI:0403”(colocalization)	0.460
DCP1A	TIA1	psi-mi:“MI:0403”(colocalization)	0.430
SNRNP70	TIA1	psi-mi:“MI:0915”(physical association)	0.400
	TIA1	psi-mi:“MI:0915”(physical association)	0.400
WBP4	TIA1	psi-mi:“MI:0915”(physical association)	0.370
RICTOR	WIZ	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
ANG	DDX39A	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
TIA1	TOB1	psi-mi:“MI:0914”(association)	0.350
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
CUL4A	HAX1	psi-mi:“MI:0914”(association)	0.350
DCUN1D1	RGSL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (153): TIA1 (Affinity Capture-MS), LUC7L2 (Co-fractionation), MPI (Co-fractionation), PCBP1 (Co-fractionation), PCBP2 (Co-fractionation), PITPNB (Co-fractionation), SNRPD1 (Co-fractionation), TIA1 (Co-fractionation), TIA1 (Co-fractionation), TIA1 (Co-fractionation), TIA1 (Co-fractionation), TIA1 (Affinity Capture-MS), TIA1 (Affinity Capture-MS), TIA1 (Affinity Capture-MS), TIA1 (Affinity Capture-MS)

ESM2 similar proteins: A2Q848, F4I3B3, O01671, O22173, O60176, P16914, P17225, P23241, P26599, P31483, P32588, P42731, P52912, P70318, Q00438, Q00539, Q01085, Q09702, Q0J9Y2, Q0V9L3, Q0WW84, Q1RMJ7, Q28F51, Q29099, Q2R0Q1, Q4KM14, Q5R462, Q6YZW2, Q7TSY6, Q80VC6, Q8CIN6, Q8GZ26, Q8LFS6, Q8VXZ9, Q8WN55, Q93W34, Q95QV8, Q9BJZ5, Q9FPJ8, Q9FXA2

Diamond homologs: A0A0A0LLY1, A2A5N3, A2VDB3, A5A6M3, A6NDE4, A6NEQ0, D4AE41, F1QB54, F4I3B3, O60176, O64380, O75526, O93235, P0C7P1, P0C8Z4, P0CB38, P0CP46, P0CP47, P0DJD3, P0DJD4, P10979, P11940, P20965, P21187, P29341, P31483, P32588, P38159, P38760, P39684, P49310, P49311, P52912, P60824, P60825, P60826, P61286, P70318, P84586, Q00539

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 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
PD-L1(CD274) glycosylation and translocation to plasma membrane	8	74.2×	2e-11
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	8	48.0×	3e-10
Maturation of spike protein	9	42.7×	7e-11
Maturation of DENV proteins	9	34.0×	3e-10
Macroautophagy	5	10.3×	4e-03
Asparagine N-linked glycosylation	9	9.7×	2e-05
Neddylation	10	8.5×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
obsolete protein N-linked glycosylation via asparagine	8	76.0×	4e-11
protein N-linked glycosylation	9	33.4×	2e-09
intrinsic apoptotic signaling pathway	6	30.3×	6e-06
autophagosome maturation	5	24.7×	2e-04
mitophagy	5	22.4×	3e-04
autophagosome assembly	5	15.8×	1e-03
G1/S transition of mitotic cell cycle	5	14.1×	2e-03
negative regulation of translation	5	13.8×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	160
Likely benign	131
Benign	38

Top pathogenic / likely-pathogenic (0)

SpliceAI

2568 predictions. Top by Δscore:

Variant	Effect	Δscore
2:70214347:A:AC	donor_gain	1.0000
2:70214348:C:CC	donor_gain	1.0000
2:70214351:AAAT:A	donor_gain	1.0000
2:70214351:AAATC:A	donor_gain	1.0000
2:70214352:A:C	donor_gain	1.0000
2:70214492:CTG:C	acceptor_gain	1.0000
2:70214495:C:CC	acceptor_gain	1.0000
2:70215365:TCTCA:T	donor_loss	1.0000
2:70215366:CTCAC:C	donor_loss	1.0000
2:70215367:TCACC:T	donor_loss	1.0000
2:70215368:CACCT:C	donor_loss	1.0000
2:70215369:ACC:A	donor_loss	1.0000
2:70215370:C:G	donor_loss	1.0000
2:70215492:AACC:A	acceptor_loss	1.0000
2:70215495:CT:C	acceptor_loss	1.0000
2:70215496:T:C	acceptor_loss	1.0000
2:70216221:AT:A	donor_gain	1.0000
2:70216222:T:TA	donor_gain	1.0000
2:70216229:T:C	donor_gain	1.0000
2:70216293:C:CC	acceptor_gain	1.0000
2:70216296:T:TC	acceptor_gain	1.0000
2:70216885:CA:C	donor_gain	1.0000
2:70216885:CACT:C	donor_gain	1.0000
2:70224514:A:AC	donor_gain	1.0000
2:70224515:C:CC	donor_gain	1.0000
2:70224515:CT:C	donor_gain	1.0000
2:70224583:ATC:A	donor_gain	1.0000
2:70224596:T:A	donor_gain	1.0000
2:70227726:GTTAC:G	donor_loss	1.0000
2:70227727:TTACT:T	donor_loss	1.0000

AlphaMissense

2556 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:70215405:T:A	K285I	1.000
2:70215408:C:A	G284V	1.000
2:70215408:C:T	G284D	1.000
2:70215409:C:A	G284C	1.000
2:70215409:C:G	G284R	1.000
2:70215410:C:A	W283C	1.000
2:70215410:C:G	W283C	1.000
2:70215411:C:G	W283S	1.000
2:70215412:A:G	W283R	1.000
2:70215412:A:T	W283R	1.000
2:70215416:G:C	C281W	1.000
2:70215417:C:T	C281Y	1.000
2:70215418:A:G	C281R	1.000
2:70215423:A:T	V279E	1.000
2:70215462:A:T	I266N	1.000
2:70215465:G:T	A265E	1.000
2:70215466:C:G	A265P	1.000
2:70215472:C:G	A263P	1.000
2:70215474:G:T	A262E	1.000
2:70215484:G:C	H259D	1.000
2:70215492:A:G	F256S	1.000
2:70216211:A:T	V254D	1.000
2:70216213:A:C	F253L	1.000
2:70216213:A:T	F253L	1.000
2:70216214:A:C	F253C	1.000
2:70216214:A:G	F253S	1.000
2:70216215:A:C	F253V	1.000
2:70216215:A:G	F253L	1.000
2:70216215:A:T	F253I	1.000
2:70216218:A:G	S252P	1.000

dbSNP variants (sampled 300 via entrez): RS1000010039 (2:70229555 T>A), RS1000048219 (2:70215794 C>G,T), RS1000050581 (2:70212000 C>T), RS1000069282 (2:70222880 C>T), RS1000079942 (2:70231016 T>C), RS1000132739 (2:70246591 A>G), RS1000175673 (2:70247861 T>C), RS1000201030 (2:70244727 C>T), RS1000206692 (2:70246883 G>A), RS1000331644 (2:70220629 A>C), RS1000414790 (2:70242415 C>A), RS1000485654 (2:70245279 G>A), RS1000510060 (2:70248815 C>G,T), RS1000562162 (2:70248639 C>G), RS1000573491 (2:70248511 T>C,G)

Disease associations

OMIM: gene MIM:603518 | disease phenotypes: MIM:604454, MIM:619133

GenCC curated gene-disease

Disease	Classification	Inheritance
distal myopathy, Welander type	Strong	Autosomal dominant
amyotrophic lateral sclerosis 26 with or without frontotemporal dementia	Moderate	Semidominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
amyotrophic lateral sclerosis 26 with or without frontotemporal dementia	Limited	AD

Mondo (2): distal myopathy, Welander type (MONDO:0011466), amyotrophic lateral sclerosis 26 with or without frontotemporal dementia (MONDO:0030885)

Orphanet (1): Distal myopathy, Welander type (Orphanet:603)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000751	Personality changes
HP:0001283	Bulbar palsy
HP:0001288	Gait disturbance
HP:0001638	Cardiomyopathy
HP:0002145	Frontotemporal dementia
HP:0002312	Clumsiness
HP:0002354	Memory impairment
HP:0002381	Aphasia
HP:0002460	Distal muscle weakness
HP:0003198	Myopathy
HP:0003376	Steppage gait
HP:0003458	EMG: myopathic abnormalities
HP:0003581	Adult onset
HP:0003584	Late onset
HP:0003596	Middle age onset
HP:0003677	Slowly progressive
HP:0003690	Limb muscle weakness
HP:0003693	Distal amyotrophy
HP:0003805	Rimmed vacuoles
HP:0007149	Distal upper limb amyotrophy
HP:0007354	Amyotrophic lateral sclerosis
HP:0008180	Mildly elevated creatine kinase
HP:0008954	Intrinsic hand muscle atrophy
HP:0008959	Distal upper limb muscle weakness
HP:0009027	Foot dorsiflexor weakness
HP:0009077	Weakness of long finger extensor muscles
HP:0011462	Young adult onset
HP:0100315	Lewy bodies

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002481_1	Acne (severe)	5.000000e-06
GCST006661_199	Male-pattern baldness	3.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066919 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.32	Kd	483.2	nM	CHEMBL5653589
6.24	ED50	572.4	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149586: Binding affinity to human TIA1 incubated for 45 mins by Kinobead based pull down assay	kd	0.4832	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	7
sodium arsenite	decreases reaction, affects binding, increases reaction, decreases expression, affects cotreatment (+2 more)	6
bisphenol A	affects expression, decreases expression	3
trichostatin A	affects cotreatment, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Doxorubicin	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenate	decreases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
nickel chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
flupirtine	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
cyclic 3’,5’-uridine monophosphate	affects binding	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
pateamine A	affects localization	1
dorsomorphin	affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652628	Binding	Binding affinity to human TIA1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 3 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B8QV	Abcam HCT 116 TIA1 KO	Cancer cell line	Male
CVCL_B9T9	Abcam A-549 TIA1 KO	Cancer cell line	Male
CVCL_D2HE	Abcam MCF-7 TIA1 KO	Cancer cell line	Female
CVCL_E4TN	KOLF2.1J TIA1 22.2kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_E7MY	KOLF2.1J TIA1 P351L SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7MZ	KOLF2.1J TIA1 P351L SNV/WT	Induced pluripotent stem cell	Male
CVCL_TS29	HAP1 TIA1 (-) 1	Cancer cell line	Male
CVCL_TS30	HAP1 TIA1 (-) 2	Cancer cell line	Male
CVCL_TS31	HAP1 TIA1 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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