TIAM1

Summary

TIAM1 (TIAM Rac1 associated GEF 1, HGNC:11805) is a protein-coding gene on chromosome 21q22.11, encoding Rho guanine nucleotide exchange factor TIAM1 (Q13009). Guanyl-nucleotide exchange factor that activates RHO-like proteins and connects extracellular signals to cytoskeletal activities.

This gene encodes a RAC1-specific guanine nucleotide exchange factor (GEF). GEFs mediate the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP). The binding of GTP induces a conformational change in RAC1 that allows downstream effectors to bind and transduce a signal. This gene thus regulates RAC1 signaling pathways that affect cell shape, migration, adhesion, growth, survival, and polarity, as well as influencing actin cytoskeletal formation, endocytosis, and membrane trafficking. This gene thus plays an important role in cell invasion, metastasis, and carcinogenesis. In addition to RAC1, the encoded protein activates additional Rho-like GTPases such as CDC42, RAC2, RAC3 and RHOA. This gene encodes multiple protein isoforms that experience a diverse array of intramolecular, protein-protein, and phosphorylation interactions as well as phosphoinositide binding. Both the longer and shorter isoforms have C-terminal Dbl homology (DH) and pleckstrin homology (PH) domains while only the longer isoforms of this gene have the N-terminal myristoylation site and the downstream N-terminal PH domain, ras-binding domain (RBD), and PSD-95/DlgA/ZO-1 (PDZ) domain.

Source: NCBI Gene 7074 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with language delay and seizures (Strong, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 365 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes
• MANE Select transcript: NM_001353694

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11805
Approved symbol	TIAM1
Name	TIAM Rac1 associated GEF 1
Location	21q22.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000156299
Ensembl biotype	protein_coding
OMIM	600687
Entrez	7074

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 16 protein_coding, 2 retained_intron

ENST00000286827, ENST00000423206, ENST00000455508, ENST00000469412, ENST00000491927, ENST00000541036, ENST00000636887, ENST00000698169, ENST00000869069, ENST00000869070, ENST00000923707, ENST00000923708, ENST00000923709, ENST00000923710, ENST00000923711, ENST00000923712, ENST00000923713, ENST00000923714

RefSeq mRNA: 12 — MANE Select: NM_001353694 NM_001353684, NM_001353685, NM_001353686, NM_001353687, NM_001353688, NM_001353689, NM_001353690, NM_001353691, NM_001353692, NM_001353693, NM_001353694, NM_003253

CCDS: CCDS13609, CCDS86983

Canonical transcript exons

ENST00000541036 — 28 exons

Exon	Start	End
ENSE00001025636	31195224	31195305
ENSE00001025637	31152636	31152761
ENSE00001025638	31153066	31153134
ENSE00001025641	31210045	31210215
ENSE00001025643	31154247	31154426
ENSE00001025648	31187001	31187087
ENSE00001025649	31182421	31182645
ENSE00001025650	31164962	31165065
ENSE00001025651	31146895	31147003
ENSE00001025653	31266010	31266983
ENSE00001025658	31202908	31203012
ENSE00001265070	31213398	31213472
ENSE00001365575	31276732	31276908
ENSE00001383160	31339243	31339422
ENSE00001610053	31141325	31141504
ENSE00001667545	31130213	31130315
ENSE00001700177	31135933	31136041
ENSE00001708609	31344138	31344261
ENSE00001722006	31141118	31141236
ENSE00001769773	31124522	31124694
ENSE00001806004	31130890	31130948
ENSE00002257089	31118418	31120837
ENSE00003540307	31225726	31225950
ENSE00003544916	31127065	31127152
ENSE00003581255	31223406	31223591
ENSE00003609954	31217553	31217699
ENSE00003624335	31245488	31245660
ENSE00003665885	31251742	31252189

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.4705 / max 897.8119, expressed in 1379 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190160	4.7913	1119
190167	2.4973	631
190168	2.2509	601
190159	1.4993	447
190145	0.4221	130
190166	0.2998	165
190161	0.1496	47
190147	0.1314	73
190142	0.1226	49
190144	0.1195	71

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	99.45	gold quality
oocyte	CL:0000023	99.41	gold quality
secondary oocyte	CL:0000655	99.12	gold quality
paraflocculus	UBERON:0005351	98.95	gold quality
cerebellum	UBERON:0002037	98.87	gold quality
cerebellar cortex	UBERON:0002129	98.78	gold quality
cerebellar hemisphere	UBERON:0002245	98.76	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.40	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.33	gold quality
middle temporal gyrus	UBERON:0002771	98.23	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.16	gold quality
upper leg skin	UBERON:0004262	97.10	gold quality
tongue squamous epithelium	UBERON:0006919	96.99	gold quality
gingival epithelium	UBERON:0001949	96.98	gold quality
tibia	UBERON:0000979	96.85	gold quality
gingiva	UBERON:0001828	96.80	gold quality
primary visual cortex	UBERON:0002436	96.51	gold quality
skin of hip	UBERON:0001554	96.25	gold quality
occipital lobe	UBERON:0002021	96.08	gold quality
entorhinal cortex	UBERON:0002728	95.52	gold quality
postcentral gyrus	UBERON:0002581	95.51	gold quality
parietal lobe	UBERON:0001872	94.95	gold quality
inferior vagus X ganglion	UBERON:0005363	94.95	gold quality
squamous epithelium	UBERON:0006914	94.80	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.79	gold quality
lower esophagus mucosa	UBERON:0035834	94.74	gold quality
esophagus squamous epithelium	UBERON:0006920	94.58	gold quality
endothelial cell	CL:0000115	94.51	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	94.51	gold quality
pons	UBERON:0000988	94.47	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	68.66
E-HCAD-25	yes	40.31
E-MTAB-9801	yes	6.07
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTBP2, ETV1, GLI1, GRHL3, KLF8, MYC

miRNA regulators (miRDB)

211 targeting TIAM1, 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-3163	100.00	77.23	8605
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834

Literature-anchored findings (GeneRIF, showing 40)

• Tiam1 is c-Myc regulator, working in the nuclei to control c-Myc-related apoptosis (PMID:12446731)
• Vav2 and Tiam1 may act as downstream effectors of Src, thereby regulating Rac1-dependent pathways that participate in Src-induced cell transformation (PMID:12810717)
• Distinct phosphoinositides regulate different functions of Tiam1. (PMID:15242348)
• expression level of Tiam1 in two giant-cell lung carcinoma cell strains with high or low metastasis potential (PMID:15295645)
• Results suggest a role for Tiam1/Rac signaling in the control of cell-cell contacts through a novel ALCAM-mediated mechanism. (PMID:15340013)
• Rap1 promotes cell spreading by localizing a subset of Rac GEFs to sites of active lamellipodia extension (PMID:15479739)
• Tiam1 gene may play an important role in invasion and metastasis of colorectal carcinoma and is a metastasis-related gene. (PMID:15655826)
• Tiam1 activates Rac and contributes to Rac signaling specificity through binding to IRSp53. (PMID:15899863)
• S1P-induced recruitment of S1P1 to CEM fractions promotes PI3 kinase-mediated Tiam1/Rac1 activation required for alpha-actinin-1/4-regulated cortical actin rearrangement and EC barrier enhancement (PMID:16195373)
• Overexpression of the Tiam1 gene correlates with invasion and metastasis of nasopharyngeal carcinoma. (PMID:16334253)
• Data suggest that strong Tiam1 overexpression relative to the corresponding benign epithelial cells is a new and independent predictor of decreased disease-free survival for patients with prostate cancer. (PMID:17003780)
• Tiam1 is overexpressed in a subset of human colorectal tumors. It affects multiple properties associated with acquisition of the metastatic phenotype & may represent a marker of colon tumor progression & metastasis in a subset of tumors. (PMID:17086355)
• Tiam1 plays a causal role in the metastasis of colorectal cancer (PMID:17132223)
• Tiam1 and betaPIX mediate OxPAPC-induced Rac activation, cytoskeletal remodeling, and barrier protective response in pulmonary endothelium (PMID:17219408)
• Tiam1 transfection in colorectal cancer cells could upregulate the expression of Fascin-1, heat shock protein 27 (HSP27), high-mobility group box 1 (HMGB1), glutathione S-transferase omega 1 (GSTO1) and downregulate the expression of annexin IV. (PMID:17376711)
• Data show that Tiam-1 gene may play an important role in invasion and metastasis of colorectal cancer. (PMID:17584632)
• CD44 is an important regulator of HGF/c-Met-mediated in vitro and in vivo barrier enhancement, a process with essential involvement of Tiam1, Rac1, dynamin 2, and cortactin. (PMID:17702746)
• Tiam1 gene plays an important role in the proliferation, invasion and metastasis of colorectal cancer. (PMID:17822624)
• 16k PRL inhibits cell migration by blocking the Ras-Tiam1-Rac1-Pak1 signaling pathway in endothelial cells (PMID:18006851)
• Results identify three genes, high-mobility group box1, annexin IV and phosphoglycerate mutase 1 that were associated with Tiam1 and may be involved in colorectal cancer metastasis. (PMID:18675922)
• Tiam1, a Rac1-specific guanine nucleotide exchange factor, was expressed mainly in the cytosol of AT2 cells exposed to mechanical strain compared with membrane localization in static cells. (PMID:18805958)
• results suggest that Rac1 and the Rac1-specific activator Tiam1 are components of transcriptionally active beta-catenin/TCF complexes at Wnt-responsive promoters, and Rac1 and Tiam1 within these complexes serves to enhance target gene transcription (PMID:18826597)
• Tiam1 expression may be a novel and independent predictor for the prognosis of hepatocellular carcinoma (PMID:18972435)
• Tiam1 counteracts the progression of breast carcinomas and is suitable as a novel breast tumor marker. (PMID:19082465)
• PAF-induced IEJ disruption and increased endothelial permeability requires the activation of a Tiam1-Rac1 signaling module, suggesting a novel therapeutic target against increased vascular permeability associated with inflammatory diseases. (PMID:19095647)
• Tiam-1 expression is closely associated with the invasiveness and metastasis of nasopharyngeal carcinoma. (PMID:19218104)
• Tiam1 is related to the metastasis of colorectal carcinoma, and may induce epithelial-mesenchymal transition to promote metastasis. (PMID:19246286)
• Overexpression of Tiam1 is associated with lymphangiogenesis in colorectal carcinoma. (PMID:19276682)
• SRC-induced disassembly of adherens junctions requires localized phosphorylation and degradation of the rac activator tiam1. (PMID:19285946)
• Upregulation of Tiam1 and Rac1 proteins may play a critical role in tumor progression of nasopharyngeal carcinoma (PMID:19506399)
• Tiam1 expression correlates with the invasion and metastasis of nasopharyngeal carcinoma cells. (PMID:19575901)
• The expression of Tiam1 was significantly higher in breast carcinomas than in normal breast tissue, and was correlated to node metastasis and clinical stage. (PMID:19923095)
• Expression of constitutively active PI3K stimulated translocation of Tiam1 to the membrane, increased Rac1 activity, and increased wound healing of airway epithelial cells. (PMID:20018857)
• results indicate that Tiam1 integrates signals from CADM1 to regulate the actin cytoskeleton through Rac activation, which may lead to tissue infiltration of leukemic cells in ATL patients (PMID:20215110)
• IRSp53 and spinophilin regulate localized Rac activation by T-lymphocyte invasion and metastasis protein 1 (PMID:20360004)
• Cell biological analysis established that Syndecan1 is a physiological binding partner of Tiam1 and that the PDZ domain has a function in cell-matrix adhesion and cell migration. (PMID:20361982)
• Mechanism for the regulation of Tiam1-mediated Rac protein activation in breast cancer. (PMID:20444703)
• regulates EphA8-ephrinA5 signaling and clathrin-mediated endocytosis (PMID:20496116)
• Increased TIAM1 is associated with vascular invasion and intrahepatic metastasis hepatocellular carcinoma. (PMID:20522449)
• Stromal Tiam1 has a role in modulating the effects of the tumor microenvironment on malignant cell invasion and metastasis. (PMID:20802514)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tiam1b	ENSDARG00000025920
danio_rerio	tiam1a	ENSDARG00000078430
mus_musculus	Tiam1	ENSMUSG00000002489
rattus_norvegicus	Tiam1	ENSRNOG00000021569

Paralogs (22): TRIO (ENSG00000038382), MCF2L2 (ENSG00000053524), PLEKHG2 (ENSG00000090924), MCF2 (ENSG00000101977), ARHGEF7 (ENSG00000102606), PLEKHG1 (ENSG00000120278), MCF2L (ENSG00000126217), ARHGEF6 (ENSG00000129675), ARHGEF9 (ENSG00000131089), VAV3 (ENSG00000134215), VAV1 (ENSG00000141968), TIAM2 (ENSG00000146426), KIAA1755 (ENSG00000149633), PLEKHG4B (ENSG00000153404), KALRN (ENSG00000160145), VAV2 (ENSG00000160293), ARHGEF40 (ENSG00000165801), SPATA13 (ENSG00000182957), SESTD1 (ENSG00000187231), PLEKHN1 (ENSG00000187583), PLEKHG4 (ENSG00000196155), ARHGEF25 (ENSG00000240771)

Protein

Protein identifiers

Rho guanine nucleotide exchange factor TIAM1 — Q13009 (reviewed: Q13009)

Alternative names: T-lymphoma invasion and metastasis-inducing protein 1

All UniProt accessions (6): Q13009, A0A1B0GW57, A0A2X0TW27, A0A8V8TN84, C9JMB5, H7C079

UniProt curated annotations — full annotation on UniProt →

Function. Guanyl-nucleotide exchange factor that activates RHO-like proteins and connects extracellular signals to cytoskeletal activities. Activates RAC1, CDC42, and to a lesser extent RHOA and their downstream signaling to regulate processes like cell adhesion and cell migration.

Subunit / interactions. Component of the Par polarity complex, composed of at least phosphorylated PRKCZ, PARD3 and TIAM1. Interacts with NTRK2; mediates the activation of RAC1 by BDNF. Interacts with MAPK8IP2 and CD44. Interacts with BAIAP2. Interacts with EPHA8; regulates clathrin-mediated endocytosis of EPHA8. Interacts with PARD3. Interacts (via PDZ domain) with CNTNAP4, SDC1 and SDC3 (via C-terminus).

Subcellular location. Cell junction. Cell membrane.

Tissue specificity. Found in virtually all analyzed tumor cell lines including B- and T-lymphomas, neuroblastomas, melanomas and carcinomas.

Post-translational modifications. Ubiquitinated. Undergoes ‘Lys-48’ ubiquitination at Lys-1404 and Lys-1420 by a CUL3(KBTBD6/7) E3 ubiquitin ligase complex composed of CUL3, RBX1, KBTBD6 and KBTBD7. ‘Lys-48’ ubiquitination at Lys-1404 and Lys-1420 triggers proteasomal degradation. Ubiquitination at Lys-1404 and Lys-1420 by CUL3(KBTBD6/7) also requires the membrane-associated protein GABARAP and may therefore be spatially restricted within the cell.

Disease relevance. Neurodevelopmental disorder with language delay and seizures (NEDLDS) [MIM:619908] An autosomal recessive disorder characterized by global developmental delay, intellectual disability, speech delay, and seizures. Additional features may include axial hypotonia, peripheral hypertonia, hypothyroidism, and non-specific dysmorphic features or brain imaging abnormalities. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The first PH domain mediates interaction with membranes enriched in phosphoinositides.

Similarity. Belongs to the TIAM family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13009-1	1	yes
Q13009-2	2

RefSeq proteins (12): NP_001340613, NP_001340614, NP_001340615, NP_001340616, NP_001340617, NP_001340618, NP_001340619, NP_001340620, NP_001340621, NP_001340622, NP_001340623, NP_003244 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR001331	GDS_CDC24_CS	Conserved_site
IPR001478	PDZ	Domain
IPR001849	PH_domain	Domain
IPR003116	RBD_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR040655	TIAM1_CC-Ex	Domain
IPR043537	Tiam1/Tiam2/Sif	Family
IPR055230	PH_Tiam1/2	Domain

Pfam: PF00169, PF00595, PF00621, PF02196, PF18385, PF23014

UniProt features (87 total): strand 16, sequence variant 12, compositionally biased region 11, helix 10, modified residue 7, sequence conflict 7, region of interest 5, domain 5, mutagenesis site 4, turn 3, cross-link 2, splice variant 2, initiator methionine 1, chain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3KZD	X-RAY DIFFRACTION	1.3
4GVC	X-RAY DIFFRACTION	1.54
3KZE	X-RAY DIFFRACTION	1.8
4GVD	X-RAY DIFFRACTION	1.85
4NXR	X-RAY DIFFRACTION	1.9
4K2P	X-RAY DIFFRACTION	1.98
4NXQ	X-RAY DIFFRACTION	2.1
4K2O	X-RAY DIFFRACTION	2.15
4NXP	X-RAY DIFFRACTION	2.3
2D8I	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13009-F1	59.82	0.22

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): 231, 356, 358, 695, 829, 1323, 1519, 2, 1404, 1420

Mutagenesis-validated functional residues (4):

Position	Phenotype
879	strongly reduces affinity for sdc1.
912	strongly reduces affinity for sdc1.
1404	decreased ubiquitination and increased abundance.
1420	decreased ubiquitination and increased abundance.

Function

Pathways and Gene Ontology

Reactome pathways

27 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-3928665	EPH-ephrin mediated repulsion of cells
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-9032845	Activated NTRK2 signals through CDK5
R-HSA-9958810	SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-166520	Signaling by NTRKs
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-194315	Signaling by Rho GTPases
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-422475	Axon guidance
R-HSA-73887	Death Receptor Signaling
R-HSA-9006115	Signaling by NTRK2 (TRKB)
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-9012999	RHO GTPase cycle
R-HSA-9675108	Nervous system development
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 536 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, E2F_Q4_01, FREAC2_01, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, HINATA_NFKB_TARGETS_KERATINOCYTE_UP, PID_ARF6_DOWNSTREAM_PATHWAY, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_UP, WANG_ESOPHAGUS_CANCER_VS_NORMAL_DN

GO Biological Process (18): cell-matrix adhesion (GO:0007160), small GTPase-mediated signal transduction (GO:0007264), positive regulation of cell population proliferation (GO:0008284), regulation of epithelial to mesenchymal transition (GO:0010717), positive regulation of epithelial to mesenchymal transition (GO:0010718), cell migration (GO:0016477), Rac protein signal transduction (GO:0016601), positive regulation of cell migration (GO:0030335), non-canonical Wnt signaling pathway (GO:0035567), ephrin receptor signaling pathway (GO:0048013), positive regulation of axonogenesis (GO:0050772), regulation of small GTPase mediated signal transduction (GO:0051056), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), protein-containing complex assembly (GO:0065003), regulation of dopaminergic neuron differentiation (GO:1904338), signal transduction (GO:0007165), intracellular signal transduction (GO:0035556), activation of GTPase activity (GO:0090630)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), lipid binding (GO:0008289), kinase binding (GO:0019900), protein binding (GO:0005515)

GO Cellular Component (8): cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), cell-cell contact zone (GO:0044291), synapse (GO:0045202), cytoplasm (GO:0005737), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
RHO GTPase cycle	5
EPH-Ephrin signaling	2
Cell death signalling via NRAGE, NRIF and NADE	1
GPCR downstream signalling	1
Signaling by NTRK2 (TRKB)	1
Activation of STAT3 by cadherin engagement	1
Signaling by Receptor Tyrosine Kinases	1
Death Receptor Signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
p75 NTR receptor-mediated signalling	1
Axon guidance	1
Signal Transduction	1
Signaling by GPCR	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
epithelial to mesenchymal transition	2
small GTPase-mediated signal transduction	2
intracellular anatomical structure	2
binding	2
cell junction	2
cell-substrate adhesion	1
intracellular signaling cassette	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of cell differentiation	1
regulation of epithelial to mesenchymal transition	1
positive regulation of cell differentiation	1
positive regulation of multicellular organismal process	1
cell motility	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
Wnt signaling pathway	1
cell surface receptor protein tyrosine kinase signaling pathway	1
axonogenesis	1
positive regulation of cell projection organization	1
positive regulation of neurogenesis	1
regulation of axonogenesis	1
regulation of intracellular signal transduction	1
non-canonical Wnt signaling pathway	1
cellular component assembly	1
protein-containing complex organization	1
regulation of neuron differentiation	1
dopaminergic neuron differentiation	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
positive regulation of GTPase activity	1
GTP binding	1
GDP binding	1

Protein interactions and networks

STRING

2120 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIAM1	NME1	P15531	953
TIAM1	RABIF	P47224	933
TIAM1	CDC42	P21181	927
TIAM1	EPHB2	P29323	927
TIAM1	IQGAP1	P46940	895
TIAM1	CD44	P16070	847
TIAM1	PARD3	Q8TEW0	835
TIAM1	NTRK2	Q16620	801
TIAM1	SDC1	P18827	788
TIAM1	TLN2	Q9Y4G6	779
TIAM1	TLN1	Q9Y490	756
TIAM1	RHOA	P06749	731
TIAM1	BDNF	P23560	712
TIAM1	PLEK2	Q9NYT0	708
TIAM1	RAC1	P15154	708
TIAM1	SNTB2	Q13425	708

IntAct

317 interactions, top by confidence:

A	B	Type	Score
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
TIAM1	CASK	psi-mi:“MI:0407”(direct interaction)	0.770
TIAM1	SDC1	psi-mi:“MI:0407”(direct interaction)	0.650
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
DLG4	TIAM1	psi-mi:“MI:0407”(direct interaction)	0.590
TIAM1	DLG4	psi-mi:“MI:0407”(direct interaction)	0.590
TIAM1	CNTNAP4	psi-mi:“MI:0407”(direct interaction)	0.560
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
PIP	TBKBP1	psi-mi:“MI:0914”(association)	0.530
Ephb2	TIAM1	psi-mi:“MI:0915”(physical association)	0.520
TIAM1	KBTBD7	psi-mi:“MI:0915”(physical association)	0.500
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
TIAM1	SDC3	psi-mi:“MI:0407”(direct interaction)	0.440
TIAM1	SDC4	psi-mi:“MI:0407”(direct interaction)	0.440
TIAM1	SDC2	psi-mi:“MI:0407”(direct interaction)	0.440
TIAM1	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
DLG1	TIAM1	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	TIAM1	psi-mi:“MI:0407”(direct interaction)	0.440
TIAM1	AHNAK	psi-mi:“MI:0407”(direct interaction)	0.440
TIAM1	APBA1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (251): TIAM1 (Affinity Capture-MS), TIAM1 (Co-fractionation), TIAM1 (Affinity Capture-Western), TIAM1 (Affinity Capture-Western), TIAM1 (Two-hybrid), TIAM1 (Proximity Label-MS), KCTD3 (Affinity Capture-MS), KIF13B (Affinity Capture-MS), ZBTB21 (Affinity Capture-MS), TIAM1 (Affinity Capture-MS), GIGYF1 (Affinity Capture-MS), LRFN1 (Affinity Capture-MS), TIAM1 (Affinity Capture-MS), TIAM1 (Affinity Capture-MS), SRGAP2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JUG7, A1L390, E9Q0S6, O08774, O14924, O15085, O43182, O54834, O54960, O60307, O75052, P57095, Q13009, Q3U1V8, Q3U214, Q3UHC7, Q4VAC9, Q5DU25, Q5JU85, Q5RBI7, Q5SXA9, Q5VWQ8, Q60610, Q64512, Q6AX33, Q6DN90, Q6NXJ0, Q6P0Q8, Q6P1I6, Q6ZMN7, Q76G19, Q76LL6, Q76M68, Q7T2V3, Q810W7, Q8CGE9, Q8IX03, Q8R0S2, Q8R4H2, Q8WYP3

Diamond homologs: A1L390, F1M0Z1, O43307, O75962, P91620, P91621, Q0KL02, Q13009, Q1ZXH8, Q3UTH8, Q4VAC9, Q58DL7, Q58EX7, Q5DU57, Q5RDK0, Q60610, Q6KAU7, Q6P720, Q6ZPF3, Q7TNR9, Q96N96, Q9H7P9, Q9NR80, Q9QX73, Q9ULL1, A1IGU3, A1IGU4, A2CG49, A8MVU1, E7F1U2, F1M707, O15068, O60229, O77774, P10911, P97924, Q09014, Q1LUA6, Q63406, Q64096

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
SRC	up-regulates	TIAM1	phosphorylation
SMO	up-regulates	TIAM1	binding
TIAM1	up-regulates	RAC1
TIAM1	“up-regulates activity”	RAC1	“guanine nucleotide exchange factor”
CSNK1A1	“down-regulates quantity by destabilization”	TIAM1	phosphorylation
MEK1/2	“down-regulates quantity by destabilization”	TIAM1	phosphorylation
SCF-betaTRCP	“down-regulates quantity by destabilization”	TIAM1	ubiquitination
SRC	“down-regulates activity”	TIAM1	phosphorylation
GRK1	“down-regulates activity”	TIAM1	phosphorylation
TIAM1	up-regulates	RAC1	binding
PPP1R9B	“up-regulates quantity”	TIAM1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 182 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	8	44.8×	2e-09
Activation of BAD and translocation to mitochondria	7	44.4×	1e-08
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	39.2×	3e-08
Ras activation upon Ca2+ influx through NMDA receptor	7	33.3×	9e-08
Activation of BH3-only proteins	7	29.0×	2e-07
RHO GTPases activate PKNs	9	23.8×	1e-08
Signaling by high-kinase activity BRAF mutants	7	18.5×	4e-06
Syndecan interactions	5	17.6×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	6	20.9×	1e-04
regulation of postsynaptic membrane neurotransmitter receptor levels	7	20.8×	4e-05
protein targeting	6	13.2×	1e-03
establishment of protein localization	5	12.9×	6e-03
substantia nigra development	5	11.0×	9e-03
intracellular protein localization	12	7.5×	4e-05
protein phosphorylation	11	4.5×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	257
Likely benign	51
Benign	15

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1693480	NM_001353694.2(TIAM1):c.983G>T (p.Gly328Val)	Pathogenic
1693481	NM_001353694.2(TIAM1):c.4640C>A (p.Ala1547Glu)	Pathogenic
1693482	NM_001353694.2(TIAM1):c.1144G>C (p.Gly382Arg)	Pathogenic
1693483	NM_001353694.2(TIAM1):c.4016C>T (p.Ala1339Val)	Pathogenic
4278093	NM_001353694.2(TIAM1):c.2003C>G (p.Ala668Gly)	Likely pathogenic

SpliceAI

9406 predictions. Top by Δscore:

Variant	Effect	Δscore
21:31130888:A:AC	donor_gain	1.0000
21:31130889:C:CC	donor_gain	1.0000
21:31130949:C:CC	acceptor_gain	1.0000
21:31141082:T:A	donor_gain	1.0000
21:31141131:CCAGT:C	donor_gain	1.0000
21:31141232:GGCCA:G	acceptor_gain	1.0000
21:31141233:GCCA:G	acceptor_gain	1.0000
21:31141234:CCA:C	acceptor_gain	1.0000
21:31141234:CCAC:C	acceptor_gain	1.0000
21:31141235:CA:C	acceptor_gain	1.0000
21:31141235:CAC:C	acceptor_gain	1.0000
21:31141236:ACTG:A	acceptor_loss	1.0000
21:31141237:C:CC	acceptor_gain	1.0000
21:31141237:C:CG	acceptor_loss	1.0000
21:31141238:T:C	acceptor_loss	1.0000
21:31141319:GCCTA:G	donor_loss	1.0000
21:31141320:CCTAC:C	donor_loss	1.0000
21:31141321:CTA:C	donor_loss	1.0000
21:31141322:TA:T	donor_loss	1.0000
21:31141323:A:AC	donor_gain	1.0000
21:31141323:A:C	donor_loss	1.0000
21:31141323:ACCGT:A	donor_gain	1.0000
21:31141324:C:CC	donor_gain	1.0000
21:31141324:CCGT:C	donor_gain	1.0000
21:31141324:CCGTC:C	donor_gain	1.0000
21:31141327:T:TA	donor_gain	1.0000
21:31141500:CTTGG:C	acceptor_gain	1.0000
21:31141501:TTGG:T	acceptor_gain	1.0000
21:31141504:GC:G	acceptor_loss	1.0000
21:31141505:C:CC	acceptor_gain	1.0000

AlphaMissense

10122 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:31141330:A:G	L1217P	1.000
21:31141372:A:G	L1203P	1.000
21:31141381:A:G	L1200P	1.000
21:31141384:A:G	L1199P	1.000
21:31141399:A:G	L1194P	1.000
21:31141404:C:A	R1192S	1.000
21:31141404:C:G	R1192S	1.000
21:31141414:G:C	P1189R	1.000
21:31141414:G:T	P1189H	1.000
21:31141418:T:C	K1188E	1.000
21:31141423:A:G	L1186P	1.000
21:31146984:C:T	G1129E	1.000
21:31146985:C:A	G1129W	1.000
21:31146987:A:G	L1128P	1.000
21:31152697:A:G	L1102P	1.000
21:31152708:G:C	F1098L	1.000
21:31152708:G:T	F1098L	1.000
21:31152709:A:G	F1098S	1.000
21:31152710:A:G	F1098L	1.000
21:31154275:A:G	L1048P	1.000
21:31154296:A:G	L1041P	1.000
21:31223457:T:A	K648N	1.000
21:31223457:T:G	K648N	1.000
21:31223569:A:G	L611P	1.000
21:31223582:A:G	W607R	1.000
21:31223582:A:T	W607R	1.000
21:31225736:A:T	I600K	1.000
21:31225784:C:T	G584D	1.000
21:31225785:C:G	G584R	1.000
21:31225787:A:C	M583R	1.000

dbSNP variants (sampled 300 via entrez): RS1000000483 (21:31540856 T>C), RS1000010790 (21:31274075 G>A), RS1000012194 (21:31208585 A>C), RS1000025235 (21:31391525 T>C), RS1000027606 (21:31339626 C>G), RS1000038793 (21:31224072 C>T), RS1000049817 (21:31348155 G>A,C), RS1000051642 (21:31464534 G>A), RS1000058656 (21:31372372 T>C), RS1000085257 (21:31195380 T>C), RS1000100342 (21:31291812 C>T), RS1000109069 (21:31353136 C>A), RS1000115302 (21:31502700 T>C), RS1000118725 (21:31469624 G>C), RS1000121810 (21:31274298 C>G,T)

Disease associations

OMIM: gene MIM:600687 | disease phenotypes: MIM:619908

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with language delay and seizures	Strong	Autosomal recessive

Mondo (1): neurodevelopmental disorder with language delay and seizures (MONDO:0859256)

Orphanet (0):

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000821	Hypothyroidism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001510	Growth delay
HP:0001629	Ventricular septal defect
HP:0002444	Hypothalamic hamartoma
HP:0002506	Diffuse cerebral atrophy
HP:0002917	Hypomagnesemia
HP:0003429	CNS hypomyelination
HP:0003593	Infantile onset
HP:0007018	Attention deficit hyperactivity disorder
HP:0008770	Obsessive-compulsive trait
HP:0008936	Axial hypotonia
HP:0011463	Childhood onset
HP:0033725	Thin corpus callosum

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001304_2	Renal sinus fat	3.000000e-06
GCST008151_25	Waist circumference	8.000000e-06
GCST008160_9	Waist circumference	8.000000e-06
GCST008476_14	Emphysema annual change measurement in smokers (percent low attenuation area)	9.000000e-06
GCST011837_1	Cervical high-risk human papilloma virus infection	2.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004864	renal sinus adipose tissue measurement
EFO:0007626	emphysema imaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3232697 (SINGLE PROTEIN), CHEMBL3301397 (PROTEIN-PROTEIN INTERACTION)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.60	IC50	2500	nM	CHEMBL3237584

PubChem BioAssay actives

1 with measured affinity, of 10 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
ethyl (1R,2R,3S,4R,6R)-2-amino-6-[3-(4-aminoanilino)phenyl]-3-phenylsulfanylbicyclo[2.2.1]heptane-2-carboxylate	1128169: Inhibition of Rac1-Tiam1 interaction in human smooth muscle cells assessed as reduction of PDGF-BB stimulated GTP bound Rac1 level preincubated for 4 hrs followed by PDGF-BB stimulation measured after 2 mins by G-LISA assay	ic50	2.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects expression	5
Estradiol	increases reaction, affects cotreatment, decreases expression, increases expression	4
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	3
bisphenol A	affects methylation, decreases methylation, increases expression	2
sodium arsenite	increases abundance, decreases expression	2
(+)-JQ1 compound	decreases expression, increases expression	2
Arsenic	decreases expression, increases abundance	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	increases expression	1
sodium arsenate	increases abundance, decreases expression	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
nickel sulfate	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
Temozolomide	increases expression	1
Acetaminophen	affects expression	1
Glyphosate	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4419261	Binding	Binding affinity to TIAM1 PH-domain (unknown origin) at 0.01 to 50 uM by SPR spectroscopy	Methods and compositions for inhibiting cnksr1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1661	ZR-75-30	Cancer cell line	Female

Clinical trials (associated diseases)

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