GAREM1

Summary

GAREM1 (GRB2 associated regulator of MAPK1 subtype 1, HGNC:26136) is a protein-coding gene on chromosome 18q12.1, encoding GRB2-associated and regulator of MAPK protein 1 (Q9H706). Acts as an adapter protein that plays a role in intracellular signaling cascades triggered either by the cell surface activated epidermal growth factor receptor and/or cytoplasmic protein tyrosine kinases.

This gene encodes an adaptor protein which functions in the epidermal growth factor (EGF) receptor-mediated signaling pathway. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 64762 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 20 total
• MANE Select transcript: NM_001242409

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26136
Approved symbol	GAREM1
Name	GRB2 associated regulator of MAPK1 subtype 1
Location	18q12.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21610
Ensembl gene	ENSG00000141441
Ensembl biotype	protein_coding
OMIM	617998
Entrez	64762

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000269209, ENST00000399218, ENST00000578619, ENST00000583696, ENST00000952371, ENST00000952372

RefSeq mRNA: 2 — MANE Select: NM_001242409 NM_001242409, NM_022751

CCDS: CCDS11905, CCDS56057

Canonical transcript exons

ENST00000269209 — 6 exons

Exon	Start	End
ENSE00000948556	32392895	32393035
ENSE00000948559	32270217	32270383
ENSE00001108179	32287031	32288203
ENSE00001269241	32263522	32268768
ENSE00001934691	32470308	32470882
ENSE00003541478	32310193	32310323

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 92.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.9080 / max 91.8324, expressed in 1200 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171600	3.6032	1078
171599	0.8756	496
171598	0.2580	123
171601	0.1482	73
171597	0.0230	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	92.78	gold quality
cartilage tissue	UBERON:0002418	91.98	gold quality
corpus callosum	UBERON:0002336	91.60	gold quality
inferior vagus X ganglion	UBERON:0005363	90.81	gold quality
palpebral conjunctiva	UBERON:0001812	90.07	gold quality
nipple	UBERON:0002030	89.91	gold quality
penis	UBERON:0000989	89.85	gold quality
germinal epithelium of ovary	UBERON:0001304	89.58	gold quality
trachea	UBERON:0003126	88.14	gold quality
parotid gland	UBERON:0001831	87.90	gold quality
dorsal root ganglion	UBERON:0000044	87.64	gold quality
renal medulla	UBERON:0000362	87.56	gold quality
cerebellar vermis	UBERON:0004720	87.47	gold quality
cervix squamous epithelium	UBERON:0006922	87.44	gold quality
mammalian vulva	UBERON:0000997	87.20	gold quality
blood vessel layer	UBERON:0004797	87.01	gold quality
cranial nerve II	UBERON:0000941	86.92	gold quality
tibia	UBERON:0000979	86.78	gold quality
mucosa of urinary bladder	UBERON:0001259	86.62	gold quality
secondary oocyte	CL:0000655	86.36	gold quality
subthalamic nucleus	UBERON:0001906	86.32	gold quality
ventral tegmental area	UBERON:0002691	86.02	gold quality
buccal mucosa cell	CL:0002336	85.89	gold quality
endothelial cell	CL:0000115	85.78	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.77	gold quality
epithelium of esophagus	UBERON:0001976	85.61	gold quality
esophagus squamous epithelium	UBERON:0006920	85.52	gold quality
amniotic fluid	UBERON:0000173	85.46	gold quality
cervix epithelium	UBERON:0004801	85.46	gold quality
squamous epithelium	UBERON:0006914	85.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	26.24
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

213 targeting GAREM1, 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-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4768-5P	100.00	69.49	2861
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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4745-5P	99.98	65.95	1028

Literature-anchored findings (GeneRIF, showing 6)

• Extracellular signal-regulated kinase activation in response to epidermal growth factor stimulation is regulated by the expression of GAREM in COS-7 and HeLa cells. (PMID:19509291)
• Data indicate that a subtype of GAREM, GAREM2, is specifically expressed in the mouse, rat, and human brain. (PMID:24003223)
• suggest that the interplay between 14-3-3, SAM domain and CABIT domain might be responsible for the distribution of GAREM1 in mammalian cells. (PMID:26164232)
• We have provided evidence that GAREM1 is involved in the PR interval of ECGs. These findings increase our understanding of the regulatory signals of heart rhythm through intracardiac ganglia of the autonomic nervous system and can be used to guide the development of a therapeutic target for heart conditions, such as atrial fibrillation. (PMID:29273731)
• the miR-128-GAREM-MAPK signaling pathway forms a critical feedback loop and mediates gastric carcinoma development (PMID:30177387)
• GAREM1 is involved in controlling body mass in mice and humans. (PMID:36084556)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	garem	ENSDARG00000017242
mus_musculus	Garem1	ENSMUSG00000042680
rattus_norvegicus	Garem1	ENSRNOG00000062552

Paralogs (1): GAREM2 (ENSG00000157833)

Protein

Protein identifiers

GRB2-associated and regulator of MAPK protein 1 — Q9H706 (reviewed: Q9H706)

Alternative names: GRB2-associated and regulator of MAPK1

All UniProt accessions (2): Q9H706, J3QRF3

UniProt curated annotations — full annotation on UniProt →

Function. Acts as an adapter protein that plays a role in intracellular signaling cascades triggered either by the cell surface activated epidermal growth factor receptor and/or cytoplasmic protein tyrosine kinases. Promotes activation of the MAPK/ERK signaling pathway. Plays a role in the regulation of cell proliferation.

Subunit / interactions. Isoform 1 interacts with EGFR. Isoform 1 interacts (via proline-rich domain and phosphorylated at Tyr-105 and Tyr-453) with GRB2 (via SH3 domains); the interaction occurs upon EGF stimulation. Isoform 1 interacts (phosphorylated at Tyr-453) with PTPN11; the interaction increases MAPK/ERK activity and does not affect the GRB2/SOS complex formation. Isoform 2 does not interact with GRB2.

Tissue specificity. Isoform 1 is ubiquitously expressed.

Post-translational modifications. On EGF stimulation, phosphorylated on Tyr-105 and Tyr-453.

Similarity. Belongs to the GAREM family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H706-1	1	yes
Q9H706-2	2, GAREM(S)
Q9H706-3	3

RefSeq proteins (2): NP_001229338, NP_073588 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR025946	CABIT_dom	Domain
IPR052281	GAREM	Family

Pfam: PF12736

UniProt features (30 total): helix 6, sequence variant 5, region of interest 5, modified residue 4, compositionally biased region 3, splice variant 2, mutagenesis site 2, chain 1, domain 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2DKZ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H706-F1	58.95	0.17

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 (4): 105, 453, 610, 614

Mutagenesis-validated functional residues (2):

Position	Phenotype
105	does not abolish phosphorylation upon egf stimulation. reduces interaction with grb2. abolishes phosphorylation, interac
453	does not abolish phosphorylation upon egf stimulation. abolishes interaction with ptpn11. abolishes phosphorylation upon

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 172 (showing top): WANG_CLIM2_TARGETS_UP, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_RESPONSE_TO_EPIDERMAL_GROWTH_FACTOR, DAVICIONI_RHABDOMYOSARCOMA_PAX_FOXO1_FUSION_UP, chr18q12, GOBP_POSITIVE_REGULATION_OF_CELL_DIVISION, GOBP_ERBB_SIGNALING_PATHWAY, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, GOBP_MULTICELLULAR_ORGANISM_GROWTH, CAIRO_HEPATOBLASTOMA_DN, GOBP_REGULATION_OF_CELL_DIVISION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (6): epidermal growth factor receptor signaling pathway (GO:0007173), positive regulation of cell population proliferation (GO:0008284), multicellular organism growth (GO:0035264), positive regulation of cell division (GO:0051781), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to epidermal growth factor stimulus (GO:0071364)

GO Molecular Function (2): proline-rich region binding (GO:0070064), protein binding (GO:0005515)

GO Cellular Component (1): plasma membrane (GO:0005886)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cellular process	2
ERBB signaling pathway	1
cell population proliferation	1
regulation of cell population proliferation	1
multicellular organismal process	1
developmental growth	1
cell division	1
regulation of cell division	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
response to epidermal growth factor	1
cellular response to growth factor stimulus	1
protein binding	1
binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

758 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GAREM1	GRB2	P29354	886
GAREM1	ARHGEF5	Q12774	689
GAREM1	TRIM51G	A0A3B3IT33	593
GAREM1	YWHAE	P29360	570
GAREM1	PTPN11	Q06124	546
GAREM1	SHC1	P29353	524
GAREM1	LRRK1	Q38SD2	476
GAREM1	ZCCHC3	Q9NUD5	470
GAREM1	THEMIS2	Q5TEJ8	465
GAREM1	RMP24	Q32NC0	448
GAREM1	CCDC178	Q5BJE1	447
GAREM1	SHANK3	Q9BYB0	410
GAREM1	AXDND1	Q5T1B0	397
GAREM1	KHDRBS1	Q07666	393
GAREM1	KRT39	Q6A163	386

IntAct

39 interactions, top by confidence:

A	B	Type	Score
GAREM1	GRB2	psi-mi:“MI:0915”(physical association)	0.940
GRB2	GAREM1	psi-mi:“MI:0915”(physical association)	0.940
GRAP2	STAMBP	psi-mi:“MI:0914”(association)	0.810
GAREM1	GRAP2	psi-mi:“MI:0915”(physical association)	0.740
GRAP2	GAREM1	psi-mi:“MI:0915”(physical association)	0.740
GAREM1	CRK	psi-mi:“MI:0915”(physical association)	0.650
CRK	GAREM1	psi-mi:“MI:0915”(physical association)	0.650
CRK	GAREM1	psi-mi:“MI:0407”(direct interaction)	0.650
NCK2	GAREM1	psi-mi:“MI:0915”(physical association)	0.560
GRB2	ARHGEF35	psi-mi:“MI:0914”(association)	0.530
GRB2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
CRK	GAREM1	psi-mi:“MI:0915”(physical association)	0.490
GAREM1	IGFN1	psi-mi:“MI:0915”(physical association)	0.370
GAREM1	CRKL	psi-mi:“MI:0915”(physical association)	0.370
CFTR	GAREM1	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
GAREM1	Acad9	psi-mi:“MI:0914”(association)	0.350
SHC1	KDM1A	psi-mi:“MI:0914”(association)	0.350
rep	VWA8	psi-mi:“MI:0914”(association)	0.350
SHC4	CHUK	psi-mi:“MI:0914”(association)	0.350
GAREM1	TNKS	psi-mi:“MI:0914”(association)	0.350
GAREM1	SCGB1D2	psi-mi:“MI:0914”(association)	0.350

BioGRID (54): GAREM (Two-hybrid), GAREM (Affinity Capture-MS), GAREM (Affinity Capture-MS), GAREM (Affinity Capture-Western), GAREM (Two-hybrid), GAREM (Two-hybrid), GAREM (Affinity Capture-MS), GAREM (Affinity Capture-MS), GAREM (Affinity Capture-MS), GAREM (Affinity Capture-MS), GAREM (Affinity Capture-MS), GAREM (Affinity Capture-MS), GAREM (Two-hybrid), GAREM (Two-hybrid), GRB2 (Two-hybrid)

ESM2 similar proteins: A1YEX3, A2AGX3, A2VE78, A7YWH3, A8MVX0, C0HAC0, D3YYM4, M0R2J8, P24278, P46933, Q00IB7, Q17RG1, Q2YDQ5, Q3UFT3, Q4VXA5, Q562E2, Q5BLK4, Q5F479, Q5R6E1, Q5SUS0, Q5SXH7, Q5XX13, Q6NRE4, Q6PCP7, Q6ZPF3, Q6ZW76, Q7ZUW7, Q7ZVU1, Q80TI1, Q8BLK9, Q8BW88, Q8C2S5, Q8C886, Q8IVF5, Q8K296, Q8K3E9, Q8K451, Q8NFN8, Q91XS1, Q96S38

Diamond homologs: Q3UFT3, Q6NRE4, Q6PAJ3, Q75VX8, Q7ZVU1, Q9H706

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	6
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4686 predictions. Top by Δscore:

Variant	Effect	Δscore
18:32126691:A:AG	acceptor_gain	1.0000
18:32126692:G:GG	acceptor_gain	1.0000
18:32126692:GACAT:G	acceptor_gain	1.0000
18:32126720:T:TA	acceptor_gain	1.0000
18:32126721:G:A	acceptor_gain	1.0000
18:32126797:TGTGG:T	donor_loss	1.0000
18:32126798:GTG:G	donor_gain	1.0000
18:32126799:TGG:T	donor_loss	1.0000
18:32126800:GGTA:G	donor_loss	1.0000
18:32126801:G:GG	donor_gain	1.0000
18:32126801:G:T	donor_loss	1.0000
18:32126802:TAAG:T	donor_loss	1.0000
18:32126803:AAGT:A	donor_loss	1.0000
18:32129114:TTTA:T	acceptor_loss	1.0000
18:32129115:TTAG:T	acceptor_loss	1.0000
18:32129117:A:AG	acceptor_gain	1.0000
18:32129117:A:G	acceptor_loss	1.0000
18:32129118:G:GA	acceptor_loss	1.0000
18:32129118:G:GG	acceptor_gain	1.0000
18:32129118:GA:G	acceptor_gain	1.0000
18:32192638:A:AG	acceptor_gain	1.0000
18:32204167:A:AG	acceptor_gain	1.0000
18:32204168:A:G	acceptor_gain	1.0000
18:32207401:G:GT	donor_gain	1.0000
18:32207422:GATT:G	donor_gain	1.0000
18:32207429:G:GG	donor_gain	1.0000
18:32207449:T:G	donor_gain	1.0000
18:32207468:GCT:G	donor_gain	1.0000
18:32207471:G:GG	donor_gain	1.0000
18:32208278:GGA:G	donor_gain	1.0000

AlphaMissense

5722 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:32267888:A:G	W872R	1.000
18:32267888:A:T	W872R	1.000
18:32268043:A:G	L820P	1.000
18:32287569:A:T	V343D	1.000
18:32287786:A:C	Y271D	1.000
18:32287940:A:C	F219L	1.000
18:32287940:A:T	F219L	1.000
18:32287941:A:C	F219C	1.000
18:32287941:A:G	F219S	1.000
18:32287942:A:G	F219L	1.000
18:32287948:C:G	G217R	1.000
18:32287965:A:G	L211P	1.000
18:32287965:A:T	L211H	1.000
18:32287973:G:C	S208R	1.000
18:32287973:G:T	S208R	1.000
18:32287975:T:G	S208R	1.000
18:32287986:C:G	R204P	1.000
18:32287997:A:C	C200W	1.000
18:32287999:A:G	C200R	1.000
18:32288004:A:G	L198P	1.000
18:32288004:A:T	L198H	1.000
18:32288008:A:G	C197R	1.000
18:32288125:C:A	G158W	1.000
18:32288125:C:G	G158R	1.000
18:32288125:C:T	G158R	1.000
18:32288136:A:G	L154P	1.000
18:32288136:A:T	L154H	1.000
18:32288154:A:G	L148P	1.000
18:32288154:A:T	L148Q	1.000
18:32310221:A:T	V122D	1.000

dbSNP variants (sampled 300 via entrez): RS1000002989 (18:32279790 T>C), RS1000005416 (18:32436718 C>T), RS1000018940 (18:32301020 T>C), RS1000027903 (18:32265763 A>G), RS1000029299 (18:32384948 T>C), RS1000039385 (18:32343314 T>G), RS1000042470 (18:32436895 G>T), RS1000045867 (18:32392348 G>C), RS1000061007 (18:32266891 T>A,C), RS1000062618 (18:32385444 C>A,G,T), RS1000097179 (18:32349444 T>C), RS1000098400 (18:32437164 T>C), RS1000101773 (18:32307173 A>G), RS1000141901 (18:32376829 A>G), RS1000147811 (18:32430283 T>C)

Disease associations

OMIM: gene MIM:617998 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002535_2	PR interval	6.000000e-08
GCST003818_6	Resting heart rate	1.000000e-08
GCST004988_658	Breast cancer	6.000000e-12
GCST006007_3	Left ventricular internal dimension in systole	5.000000e-08
GCST006008_3	Left ventricular internal dimension in diastole	5.000000e-08
GCST010242_248	HDL cholesterol levels	1.000000e-08
GCST010256_3	Diastolic blood pressure x quantitative lifestyle risk score interaction (2df test)	2.000000e-06
GCST010257_2	Diastolic blood pressure x quantitative lifestyle risk score interaction (1df test)	7.000000e-07
GCST010258_3	Diastolic blood pressure	2.000000e-06
GCST010320_123	PR interval	4.000000e-14
GCST010321_169	PR interval	2.000000e-06
GCST010321_61	PR interval	2.000000e-18

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004462	PR interval
EFO:0008206	left ventricular systolic function measurement
EFO:0008204	left ventricular diastolic function measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0006336	diastolic blood pressure
EFO:0010724	lifestyle measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
Acetaminophen	increases expression	2
Valproic Acid	decreases expression, affects expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol A	increases expression	1
terbufos	increases methylation	1
arsenite	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Arbutin	increases expression	1
Vehicle Emissions	decreases expression, decreases reaction	1
Caffeine	increases phosphorylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Fonofos	increases methylation	1
Estradiol	increases expression, affects cotreatment	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	affects expression	1
Lead	affects expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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