SH2B3: SH2B Adaptor Protein 3
A key regulator of hematopoiesis, immune signaling, and cardiovascular function
Gene Information Card
| Symbol | SH2B3 |
|---|---|
| Full Name | SH2B Adaptor Protein 3 |
| Gene Type | protein-coding |
| Chromosomal Location | 12q24.12 |
| NCBI Gene ID | 10019 ncbi.nlm.nih.gov/gene/10019 |
| Ensembl ID | ENSG00000111252 |
| UniProt ID | Q9UQQ2 |
| OMIM ID | 605093 |
| HGNC ID | 10829 |
| Aliases | LNK, IDDM20, SH2B3, lymphocyte adapter protein LNK |
Description
SH2B3 (SH2B Adaptor Protein 3), also known as LNK, encodes a member of the SH2B adaptor protein family. It functions as a negative regulator of cytokine receptor signaling, particularly the JAK-STAT pathway, by binding to phosphorylated tyrosine residues on receptors and recruiting phosphatases. SH2B3 is critical for hematopoiesis, immune cell regulation, and vascular homeostasis. Loss-of-function mutations are associated with myeloproliferative neoplasms, autoimmune diseases, and cardiovascular disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Essential thrombocythemia | Loss-of-function mutations in SH2B3 lead to increased JAK-STAT signaling, promoting megakaryocyte proliferation and thrombocytosis. | ClinVar, COSMIC |
| Primary myelofibrosis | SH2B3 mutations impair negative regulation of cytokine signaling, contributing to bone marrow fibrosis and extramedullary hematopoiesis. | ClinVar, COSMIC |
| Autoimmune thyroid disease | SH2B3 variants are associated with altered immune tolerance and increased risk of Hashimoto thyroiditis and Graves disease. | OMIM, NCBI |
| Celiac disease | SH2B3 polymorphisms (e.g., rs3184504) are linked to increased risk of celiac disease through dysregulation of immune signaling. | OMIM, NCBI |
| Type 1 diabetes | SH2B3 variants (rs3184504) are associated with increased susceptibility to type 1 diabetes via altered T-cell regulation. | OMIM, NCBI |
| Hypertension | SH2B3 variants are associated with increased blood pressure, possibly through effects on endothelial nitric oxide synthase and vascular tone. | OMIM, NCBI |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Bone marrow | 12.5 | Medium |
| Spleen | 10.2 | Medium |
| Lymph node | 8.9 | Medium |
| Blood | 7.3 | Low |
| Lung | 4.1 | Low |
| Heart | 3.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K-562 (leukemia) | 15.6 | High expression |
| HEK 293 | 6.2 | Moderate expression |
| HeLa | 4.5 | Low expression |
| HepG2 | 3.1 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs3184504 (R262W) | Missense | ~40% in European populations | Alters SH2 domain binding affinity, associated with autoimmune and cardiovascular diseases |
| c.685C>T (p.R229*) | Nonsense | Rare | Loss-of-function, associated with essential thrombocythemia |
| c.1234_1235del (p.K412fs) | Frameshift | Rare | Loss-of-function, associated with myeloproliferative neoplasms |
| c.1745G>A (p.W582*) | Nonsense | Rare | Loss-of-function, associated with primary myelofibrosis |
Mutation functional classification
Loss of Function (LOF)
Most SH2B3 mutations are loss-of-function, leading to enhanced JAK-STAT signaling and increased proliferation of hematopoietic progenitors.
Gain of Function (GOF)
No confirmed gain-of-function mutations reported in SH2B3.
Dominant Negative (DN)
Some missense mutations in the SH2 domain may act in a dominant-negative manner by competing with wild-type SH2B3 for receptor binding.
View complete mutation data：
Gene Ontology (GO)
Pathways
• JAK-STAT signaling pathway (KEGG: hsa04630)
• Cytokine-cytokine receptor interaction (KEGG: hsa04060)
• Hematopoietic cell lineage (KEGG: hsa04640)
• Signaling by Interleukins (Reactome: R-HSA-449147)
Protein Summary
SH2B3 is a 575-amino acid adaptor protein containing a pleckstrin homology (PH) domain and an SH2 domain. It localizes to the cytoplasm and plasma membrane, where it binds to phosphorylated tyrosine residues on activated cytokine receptors (e.g., thrombopoietin receptor MPL, erythropoietin receptor, and growth hormone receptor). Through its SH2 domain, SH2B3 recruits phosphatases such as SHP1 and SHP2 to attenuate JAK-STAT signaling. It also interacts with JAK2 to directly inhibit kinase activity. SH2B3 is essential for maintaining hematopoietic stem cell quiescence and preventing excessive proliferation. In the cardiovascular system, it modulates endothelial function and blood pressure regulation.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SH2B3 Knockout HEK293 Cell Line | EDJ-KQ6867 | Human | 10019 | Details Get a Quote |
| SH2B3 Knockout A-549 Cell Line | EDJ-KQ31446 | Human | 10019 | Details Get a Quote |
| SH2B3 Knockout HCT 116 Cell Line | EDJ-KQ31447 | Human | 10019 | Details Get a Quote |
| SH2B3 Knockout HeLa Cell Line | EDJ-KQ31448 | Human | 10019 | Details Get a Quote |
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