JAK2 Gene: Structure, Function, and Clinical Significance
A comprehensive guide to the JAK2 gene, its role in hematopoiesis, associated diseases, and mutation landscape.
Gene Information Card
| Symbol | JAK2 |
|---|---|
| Full Name | Janus Kinase 2 |
| Gene Type | Protein coding |
| Chromosomal Location | 9p24.1 |
| NCBI Gene ID | 3717 ncbi.nlm.nih.gov/gene/3717 |
| Ensembl ID | ENSG00000096968 |
| UniProt ID | O60674 |
| OMIM ID | 147796 |
| HGNC ID | 6192 |
| Aliases | JTK10, THCYT3 |
Description
The JAK2 gene encodes a non-receptor tyrosine kinase that plays a central role in cytokine and growth factor signaling. It is essential for hematopoiesis, immune responses, and cellular growth. JAK2 associates with various cytokine receptors and phosphorylates STAT proteins, leading to gene transcription. Mutations in JAK2, particularly the V617F gain-of-function mutation, are strongly associated with myeloproliferative neoplasms (MPNs) such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Polycythemia Vera | Gain-of-function mutation (V617F) leads to constitutive activation of JAK-STAT signaling, causing uncontrolled erythroid proliferation. | Somatic mutation found in >95% of PV cases (Baxter et al., 2005; James et al., 2005). |
| Essential Thrombocythemia | JAK2 V617F mutation promotes megakaryocyte proliferation and platelet overproduction. | Present in ~50-60% of ET cases (Kralovics et al., 2005). |
| Primary Myelofibrosis | JAK2 V617F mutation drives abnormal myeloid proliferation and fibrosis, with altered cytokine signaling. | Found in ~50% of PMF cases (Levine et al., 2005). |
| Acute Lymphoblastic Leukemia (ALL) | JAK2 rearrangements (e.g., BCR-JAK2) or mutations (e.g., R683G) activate JAK-STAT signaling, contributing to leukemogenesis. | Rare but recurrent in ALL, especially in Down syndrome-associated ALL (Bercovich et al., 2008). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Bone Marrow | High | High expression in hematopoietic stem and progenitor cells. |
| Spleen | Medium | Expression in splenic tissue, particularly in red pulp. |
| Thymus | Medium | Expression in T-cell progenitors. |
| Lymph Node | Medium | Expression in immune cells. |
| Peripheral Blood | High | Expression in leukocytes. |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K562 | High | Chronic myeloid leukemia cell line; JAK2 expression is elevated. |
| HEL | High | Erythroleukemia cell line; harbors JAK2 V617F mutation. |
| Jurkat | Medium | T-cell leukemia cell line; JAK2 expression present. |
| U937 | Medium | Histiocytic lymphoma cell line; JAK2 expression moderate. |
| MCF7 | Low | Breast cancer cell line; JAK2 expression lower compared to hematopoietic lines. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| V617F | Missense (G->T at nucleotide 1849) | ~95% in PV, ~50-60% in ET and PMF | Gain-of-function: constitutive kinase activation, leading to cytokine-independent signaling. |
| Exon 12 mutations (e.g., N542-E543del) | In-frame deletions/insertions | ~2-5% in PV (often JAK2 V617F-negative) | Gain-of-function: similar to V617F, causing constitutive activation. |
| R683G | Missense | Rare in ALL (especially Down syndrome-associated) | Gain-of-function: enhances kinase activity and STAT activation. |
| T875N | Missense | Rare in MPN | Gain-of-function: increases kinase activity. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in JAK2 are rare and typically associated with immune deficiency. For example, mutations in the pseudokinase domain can impair kinase activity, leading to reduced STAT signaling and defective cytokine responses. Such mutations have been reported in some cases of severe combined immunodeficiency (SCID) or other immunodeficiencies.
Gain of Function (GOF)
Gain-of-function mutations, particularly V617F and exon 12 mutations, are common in MPNs. These mutations disrupt the autoinhibitory pseudokinase domain, leading to constitutive kinase activity, JAK-STAT pathway activation, and cytokine-independent cell proliferation.
Dominant Negative (DN)
Dominant-negative mutations in JAK2 are not well-documented. However, some mutations may produce truncated proteins that interfere with wild-type JAK2 function, potentially acting in a dominant-negative manner, but evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • protein tyrosine kinase activity | • ATP binding |
| • signal transduction | • cytokine-mediated signaling pathway |
| • JAK-STAT cascade | • receptor signaling protein tyrosine kinase activity |
| • cell proliferation | • positive regulation of cell population proliferation |
| • phosphorylation | • innate immune response |
Pathways
• JAK-STAT signaling pathway
• Cytokine-cytokine receptor interaction
• Hematopoietic cell lineage
• Prolactin signaling pathway
• Growth hormone signaling pathway
• ErbB signaling pathway
• PDGF signaling pathway
Protein Summary
The JAK2 protein is a 1132-amino acid tyrosine kinase with a molecular weight of ~130 kDa. It contains four key domains: an N-terminal FERM domain (mediates receptor binding), a SH2-like domain, a pseudokinase domain (regulatory), and a C-terminal kinase domain (catalytic). JAK2 associates with type I and type II cytokine receptors. Upon ligand binding, JAK2 autophosphorylates and phosphorylates receptor tyrosine residues, creating docking sites for STAT proteins. STATs are then phosphorylated, dimerize, and translocate to the nucleus to regulate gene expression. JAK2 is critical for erythropoietin, thrombopoietin, and growth hormone signaling. Dysregulation of JAK2 is implicated in multiple cancers and inflammatory conditions.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| JAK2 Knockout HEK293 Cell Line | EDJ-KQ17828 | Human | 3717 | Details Get a Quote |
| JAK2 Knockout A-549 Cell Line | EDJ-KQ18825 | Human | 3717 | Details Get a Quote |
| JAK2 Knockout HCT 116 Cell Line | EDJ-KQ18826 | Human | 3717 | Details Get a Quote |
| JAK2 Knockout HeLa Cell Line | EDJ-KQ18827 | Human | 3717 | Details Get a Quote |
| JAK2 (p.H163=) Point Mutation in HAP1 Cell Line | EDC03515 | Human | 3717 | Details Get a Quote |
| JAK2 (p.L830=) Point Mutation in HAP1 Cell Line | EDC03516 | Human | 3717 | Details Get a Quote |
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