SH2B2

Summary

SH2B2 (SH2B adaptor protein 2, HGNC:17381) is a protein-coding gene on chromosome 7q22.1, encoding SH2B adapter protein 2 (O14492). Adapter protein for several members of the tyrosine kinase receptor family.

The protein encoded by this gene is expressed in B lymphocytes and contains pleckstrin homology and src homology 2 (SH2) domains. In Burkitt’s lymphoma cell lines, it is tyrosine-phosphorylated in response to B cell receptor stimulation. Because it binds Shc independent of stimulation and Grb2 after stimulation, it appears to play a role in signal transduction from the receptor to the Shc/Grb2 pathway.

Source: NCBI Gene 10603 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 10 total
• MANE Select transcript: NM_001359228

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17381
Approved symbol	SH2B2
Name	SH2B adaptor protein 2
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	APS
Ensembl gene	ENSG00000160999
Ensembl biotype	protein_coding
OMIM	605300
Entrez	10603

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 19 protein_coding, 1 nonsense_mediated_decay

ENST00000444095, ENST00000536178, ENST00000617975, ENST00000886969, ENST00000886970, ENST00000886971, ENST00000886972, ENST00000886973, ENST00000886974, ENST00000886975, ENST00000886976, ENST00000886977, ENST00000886978, ENST00000917936, ENST00000917937, ENST00000917938, ENST00000917939, ENST00000969924, ENST00000969925, ENST00000969926

RefSeq mRNA: 11 — MANE Select: NM_001359228 NM_001359228, NM_001359229, NM_001359230, NM_001359231, NM_001393990, NM_001393991, NM_001393992, NM_001393993, NM_001393994, NM_001393995, NM_001394426

CCDS: CCDS78264

Canonical transcript exons

ENST00000444095 — 9 exons

Exon	Start	End
ENSE00002472396	102317187	102317395
ENSE00002474158	102320331	102320502
ENSE00002480538	102321299	102321711
ENSE00003560661	102300522	102301279
ENSE00003729802	102286868	102287094
ENSE00003731295	102314512	102314682
ENSE00003757009	102308815	102308906
ENSE00003757119	102306721	102306822
ENSE00003758438	102314336	102314427

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 93.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.7787 / max 453.8560, expressed in 1088 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80242	3.2907	926
80241	1.4562	195
80240	0.8155	197
204619	0.1158	33
80244	0.0899	21
80243	0.0054	5
204620	0.0052	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
triceps brachii	UBERON:0001509	93.90	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.75	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.45	gold quality
biceps brachii	UBERON:0001507	93.14	gold quality
vastus lateralis	UBERON:0001379	93.03	gold quality
quadriceps femoris	UBERON:0001377	92.65	gold quality
olfactory bulb	UBERON:0002264	92.19	gold quality
skeletal muscle tissue	UBERON:0001134	91.95	gold quality
renal medulla	UBERON:0000362	91.92	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.77	gold quality
diaphragm	UBERON:0001103	91.70	gold quality
tibialis anterior	UBERON:0001385	91.22	gold quality
body of tongue	UBERON:0011876	91.01	gold quality
ventral tegmental area	UBERON:0002691	91.00	gold quality
pylorus	UBERON:0001166	90.81	gold quality
cardia of stomach	UBERON:0001162	90.66	silver quality
gluteal muscle	UBERON:0002000	90.60	gold quality
gastrocnemius	UBERON:0001388	90.14	gold quality
nipple	UBERON:0002030	90.13	gold quality
deltoid	UBERON:0001476	90.01	gold quality
subthalamic nucleus	UBERON:0001906	89.84	silver quality
muscle organ	UBERON:0001630	89.83	gold quality
superior surface of tongue	UBERON:0007371	89.73	gold quality
tongue	UBERON:0001723	89.62	gold quality
CA1 field of hippocampus	UBERON:0003881	89.54	gold quality
inferior vagus X ganglion	UBERON:0005363	89.15	silver quality
lateral globus pallidus	UBERON:0002476	89.08	silver quality
muscle of leg	UBERON:0001383	88.81	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.79	silver quality
substantia nigra pars compacta	UBERON:0001965	88.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.99

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PTEN

Literature-anchored findings (GeneRIF, showing 3)

• We present here a novel stimulatory mechanism of Vav3 in which APS directly relieves the autoinhibitory CH domain and furthermore enhances its tyrosine phosphorylation by Lck. (PMID:12400014)
• N-terminal residues distal to the phosphotyrosine directly contact residues of the four-helix bundle of the TKB domain of the adapter protein APS (PMID:15737992)
• Studies indicate that insulin receptor (IR) and IGF Type 1 Receptor (IGFR) have been identified as important partners of Grb10/14 and SH2B1/B2 adaptors. (PMID:23190452)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	SH2B2	ENSDARG00000090421
mus_musculus	Sh2b2	ENSMUSG00000005057
rattus_norvegicus	Sh2b2	ENSRNOG00000001425
drosophila_melanogaster	Lnk	FBGN0028717

Paralogs (2): SH2B3 (ENSG00000111252), SH2B1 (ENSG00000178188)

Protein

Protein identifiers

SH2B adapter protein 2 — O14492 (reviewed: O14492)

Alternative names: Adapter protein with pleckstrin homology and Src homology 2 domains, SH2 and PH domain-containing adapter protein APS

All UniProt accessions (3): O14492, A0A087X016, C9JK89

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways. May be involved in coupling from immunoreceptor to Ras signaling. Acts as a negative regulator of cytokine signaling in collaboration with CBL. Binds to EPOR and suppresses EPO-induced STAT5 activation, possibly through a masking effect on STAT5 docking sites in EPOR. Suppresses PDGF-induced mitogenesis. May induce cytoskeletal reorganization via interaction with VAV3.

Subunit / interactions. Homodimer. Interacts with KIT/c-KIT, SHC1, EPOR, PDGFR, VAV1 and VAV3. Interacts (via N-terminal region) with SHC1. Interacts (via the phosphorylated C-terminus) with GRB2. Interacts (via its SH2 domain) with EPOR, INSR and KIT. Interacts with GRB2 after B-cell antigen receptor stimulation. Interacts (via PH domain) with VAV3. Interacts with NTRK1, NTRK2 and NTRK3 (phosphorylated); after stimulation of the receptor by its extracellular ligand and subsequent autophosphorylation of the receptor. Binds INSR, GRB2, ASB6 and CAP. Insulin stimulation leads to dissociation of CAP. Binds CBS only when SH2B2/APS has become phosphorylated. INSR binding does not depend on the phosphorylation of SH2B2/APS.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in spleen, prostate, testis, uterus, small intestine and skeletal muscle. Among hematopoietic cell lines, expressed exclusively in B-cells. Not expressed in most tumor cell lines.

Post-translational modifications. Tyrosine phosphorylated by JAK2, KIT and other kinases activated by B-cell receptor in response to stimulation with cytokines, IL3, IL5, PDGF, IGF1, IGF2, CSF2/GM-CSF and cross-linking of the B-cell receptor complex.

Similarity. Belongs to the SH2B adapter family.

Isoforms (2)

UniProt ID	Names	Canonical?
O14492-1	1	yes
O14492-2	2

RefSeq proteins (11): NP_001346157, NP_001346158, NP_001346159, NP_001346160, NP_001380919, NP_001380920, NP_001380921, NP_001380922, NP_001380923, NP_001380924, NP_001381355 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR015012	Phe_ZIP	Domain
IPR030523	SH2B	Family
IPR035058	SH2B2_SH2	Domain
IPR036290	Phe_ZIP_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily

Pfam: PF00017, PF00169, PF08916

UniProt features (19 total): modified residue 4, compositionally biased region 4, helix 3, region of interest 3, domain 2, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1Q2H	X-RAY DIFFRACTION	1.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14492-F1	63.85	0.29

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): 52, 141, 310, 629

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1433559	Regulation of KIT signaling
R-HSA-983231	Factors involved in megakaryocyte development and platelet production
R-HSA-109582	Hemostasis
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-162582	Signal Transduction
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 182 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_B_CELL_HOMEOSTASIS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_LYMPHOCYTE_HOMEOSTASIS, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_RUFFLE, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_75, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_RESPONSE_TO_INSULIN, GOMF_SH2_DOMAIN_BINDING, GOBP_BROWN_FAT_CELL_DIFFERENTIATION

GO Biological Process (10): B-1 B cell homeostasis (GO:0001922), insulin receptor signaling pathway (GO:0008286), cytokine-mediated signaling pathway (GO:0019221), actin cytoskeleton organization (GO:0030036), intracellular signal transduction (GO:0035556), antigen receptor-mediated signaling pathway (GO:0050851), B cell receptor signaling pathway (GO:0050853), brown fat cell differentiation (GO:0050873), signal transduction (GO:0007165), regulation of immune response (GO:0050776)

GO Molecular Function (4): transmembrane receptor protein tyrosine kinase adaptor activity (GO:0005068), signaling adaptor activity (GO:0035591), SH2 domain binding (GO:0042169), protein binding (GO:0005515)

GO Cellular Component (7): stress fiber (GO:0001725), ruffle (GO:0001726), cytoplasm (GO:0005737), cytosol (GO:0005829), actin filament (GO:0005884), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by SCF-KIT	1
Hemostasis	1
Signaling by Receptor Tyrosine Kinases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell surface receptor protein tyrosine kinase signaling pathway	2
intracellular anatomical structure	2
B cell homeostasis	1
cellular response to insulin stimulus	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
cytoskeleton organization	1
actin filament-based process	1
signal transduction	1
immune response-activating cell surface receptor signaling pathway	1
antigen receptor-mediated signaling pathway	1
fat cell differentiation	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of immune system process	1
immune response	1
regulation of response to stimulus	1
signaling receptor complex adaptor activity	1
receptor tyrosine kinase binding	1
protein-macromolecule adaptor activity	1
protein domain specific binding	1
binding	1
actomyosin	1
contractile actin filament bundle	1
cell leading edge	1
plasma membrane bounded cell projection	1
cytoplasm	1
actin cytoskeleton	1
polymeric cytoskeletal fiber	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

518 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH2B2	CBL	P22681	566
SH2B2	GRB10	Q13322	521
SH2B2	F8VP50	F8VP50	507
SH2B2	KIT	P10721	444
SH2B2	CD79B	P40259	429
SH2B2	CD79A	P11912	424
SH2B2	SMIM17	P0DL12	382
SH2B2	PLEK2	Q9NYT0	378
SH2B2	PLEK	P08567	349
SH2B2	RHOQ	P17081	343
SH2B2	NUDT14	O95848	335
SH2B2	JAK2	O60674	330
SH2B2	IRS2	Q9Y4H2	305
SH2B2	GRB14	Q14449	304
SH2B2	IRS1	P35568	282

IntAct

19 interactions, top by confidence:

A	B	Type	Score
CBL	SH2B2	psi-mi:“MI:0914”(association)	0.660
CBL	SH2B2	psi-mi:“MI:0915”(physical association)	0.660
SH2B2	CBL	psi-mi:“MI:0915”(physical association)	0.660
SH2B2	CBL	psi-mi:“MI:0407”(direct interaction)	0.660
WDR83	SH2B2	psi-mi:“MI:0914”(association)	0.530
SH2B2	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.440
SH2B2	MET	psi-mi:“MI:0407”(direct interaction)	0.440
WDR83	PIKFYVE	psi-mi:“MI:0914”(association)	0.350
PRPS2	SMCHD1	psi-mi:“MI:0914”(association)	0.350
PRPS2	ARHGEF37	psi-mi:“MI:0914”(association)	0.350
SH2B2	JAK2	psi-mi:“MI:0914”(association)	0.350
SH2B2	PDGFRB	psi-mi:“MI:0914”(association)	0.350
LTK	AIP	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (63): SH2B2 (Affinity Capture-MS), SH2B2 (Affinity Capture-MS), SH2B2 (Affinity Capture-MS), SH2B2 (Affinity Capture-RNA), SH2B2 (Protein-RNA), SH2B2 (Two-hybrid), SH2B2 (Two-hybrid), SH2B2 (Two-hybrid), SH2B2 (Two-hybrid), SH2B2 (Two-hybrid), SH2B2 (Two-hybrid), SH2B2 (Two-hybrid), SH2B2 (Two-hybrid), SH2B2 (Two-hybrid), SH2B2 (Two-hybrid)

ESM2 similar proteins: A2A699, A2A9T0, A2AEV7, A2AJA9, A6NKL6, A6NL88, A7MCY6, A8MVW0, C9J069, E9PZZ1, J3QNX5, O14492, O14511, O15169, O35615, O43541, O94983, P0C7U0, Q02779, Q03484, Q148V8, Q3SX20, Q5BJT1, Q5JTD0, Q5JU85, Q63HR2, Q66H43, Q66L44, Q69YU3, Q6DG50, Q6PDH0, Q6R6L0, Q6ZRV2, Q75VX8, Q7TN12, Q80VC9, Q80Y50, Q86UU1, Q8C3Q5, Q8C8T7

Diamond homologs: O09039, O14492, O45539, O70142, O88834, P00519, P00520, P00521, P00522, P09760, P10447, P29353, P32577, P41239, P41240, P41241, P41242, P41243, P42679, P42684, P50745, P98077, P98083, Q08CX2, Q0IIE2, Q0VBZ0, Q5M824, Q5R7W7, Q62270, Q62985, Q6S5L8, Q8AY68, Q8BMC3, Q8IPW2, Q91ZM2, Q9H3Y6, Q9JID9, Q9JLM9, Q9NRF2, Q9UQQ2

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
SH2B2	up-regulates	CBL	binding
SH2B2	down-regulates	INSR	binding
PTEN	“up-regulates quantity by expression”	SH2B2	“transcriptional regulation”
NTRK1	up-regulates	SH2B2	phosphorylation
AKT	“up-regulates activity”	SH2B2	phosphorylation
AKT	unknown	SH2B2	phosphorylation
AKT1	“up-regulates activity”	SH2B2	phosphorylation
AKT1	unknown	SH2B2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1550 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000177734 (7:102296464 G>T), RS1000270351 (7:102302796 T>A), RS1000282056 (7:102302524 C>A), RS1000606424 (7:102301559 C>T), RS1000719659 (7:102307084 C>T), RS1000870704 (7:102312491 A>G), RS1000980135 (7:102312198 C>T), RS1001273213 (7:102303931 C>A,T), RS1001540613 (7:102314825 G>A), RS1001591210 (7:102314544 G>T), RS1001870918 (7:102313696 C>T), RS1001882103 (7:102309489 T>C,G), RS1001923299 (7:102313403 G>A,C), RS1002077253 (7:102318625 C>A,G), RS1002470028 (7:102298096 G>A)

Disease associations

OMIM: gene MIM:605300 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008114_5	Type 2 diabetes	9.000000e-06
GCST012227_136	Hip circumference adjusted for BMI	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	2
Ozone	affects expression, increases abundance, affects cotreatment, decreases expression	2
FR900359	increases phosphorylation	1
urushiol	increases expression	1
triphenyl phosphate	affects expression	1
hydroxyhydroquinone	decreases expression	1
aflatoxin B2	decreases methylation	1
tamibarotene	increases expression	1
abrine	decreases expression	1
Aripiprazole	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, affects expression	1
Arsenic	affects expression, affects methylation	1
Cadmium	increases expression	1
Niclosamide	increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3GX	Abcam HEK293T SH2B2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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