SH2B1: A Key Adapter Protein in Leptin and Insulin Signaling
Comprehensive gene overview of SH2B1, including its role in obesity, insulin resistance, and cancer.
Gene Information Card
| Symbol | SH2B1 |
|---|---|
| Full Name | SH2B adaptor protein 1 |
| Gene Type | protein-coding |
| Chromosomal Location | 16p11.2 |
| NCBI Gene ID | 25970 ncbi.nlm.nih.gov/gene/25970 |
| Ensembl ID | ENSG00000178104 |
| UniProt ID | Q9NRF2 |
| OMIM ID | 608937 |
| HGNC ID | 10817 |
| Aliases | SH2B, SH2-B, PSM, SH2B1beta, SH2B1gamma |
Description
SH2B1 (SH2B adaptor protein 1) is a cytoplasmic adapter protein that plays a critical role in receptor tyrosine kinase and cytokine receptor signaling, particularly for leptin (LEPR) and insulin (INSR) receptors. It enhances JAK2 activity and is essential for energy homeostasis, body weight regulation, and glucose metabolism. Mutations and copy-number variations in SH2B1 are associated with severe obesity, insulin resistance, and neurodevelopmental disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Obesity, severe, susceptibility to | Loss-of-function variants impair leptin signaling, leading to hyperphagia and weight gain | OMIM #608937; PMID: 17676049 |
| Type 2 diabetes | Impaired insulin signaling due to SH2B1 deficiency contributes to insulin resistance | PMID: 15247260 |
| 16p11.2 deletion syndrome (obesity-associated) | Haploinsufficiency of SH2B1 within the 16p11.2 BP2-BP3 deletion leads to early-onset obesity | PMID: 20081859 |
| Neurodevelopmental delay | SH2B1 deletion associated with intellectual disability and behavioral abnormalities | PMID: 20081859 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | Medium |
| Adipose tissue | 8.3 | Low |
| Liver | 6.1 | Low |
| Pancreas | 7.8 | Low |
| Muscle | 5.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 15.2 | Moderate expression |
| HepG2 | 9.8 | Low expression |
| SH-SY5Y | 18.7 | Moderate expression |
| 3T3-L1 (adipocyte) | 11.3 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.428C>T (p.Thr143Ile) | Missense | Rare | Impaired JAK2 binding and leptin signaling |
| c.749G>A (p.Arg250His) | Missense | Rare | Reduced insulin receptor interaction |
| 16p11.2 deletion (encompassing SH2B1) | Copy-number loss | 0.5% in obese cohorts | Haploinsufficiency, severe obesity |
Mutation functional classification
Loss of Function (LOF)
Missense variants (e.g., Thr143Ile) disrupt SH2 domain binding to JAK2, reducing leptin and insulin signaling.
Gain of Function (GOF)
Not reported in human disease; overexpression in vitro enhances JAK2 activity.
Dominant Negative (DN)
Not described for SH2B1.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Leptin signaling pathway (Reactome: R-HSA-2586552)
• Insulin receptor signaling cascade (Reactome: R-HSA-74751)
• JAK-STAT signaling (KEGG: hsa04630)
Protein Summary
SH2B1 is a 756-amino-acid adapter protein containing an N-terminal dimerization domain, a central pleckstrin homology (PH) domain, and a C-terminal SH2 domain. It binds to phosphorylated tyrosine residues on activated receptors (e.g., LEPR, INSR) and JAK2, enhancing downstream signaling. SH2B1 also promotes actin cytoskeletal reorganization and cell migration. Alternative splicing generates isoforms (beta, gamma) with tissue-specific functions.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SH2B1 Knockout HEK293 Cell Line | EDJ-KQ7656 | Human | 25970 | Details Get a Quote |
| SH2B1 Knockout A-549 Cell Line | EDJ-KQ34341 | Human | 25970 | Details Get a Quote |
| SH2B1 Knockout HCT 116 Cell Line | EDJ-KQ34343 | Human | 25970 | Details Get a Quote |
| SH2B1 Knockout HeLa Cell Line | EDJ-KQ34344 | Human | 25970 | Details Get a Quote |
