Alt. symbols: JAK1B | JAK1A | JTK3

Approved name: Janus kinase 1
Alt. names: tyrosineprotein kinase JAK1

Location: 1p31.3: 64833223 - 65067754 (-)
Gene type: protein_coding, 31 transcripts.

Scores: LoFtool: 0.168000 | pLI: 0.99590968 | LOEUF: 0.214

HGNC: 6190

NCBI: 3716, RefSeq: NG_023402.2

Ensembl: ENSG00000162434.14

LRG_1398 | Status: public

OMIM: 147795

Expression | ProteinAtlas

JAK1 encodes a Janus kinase (JAK) non-receptor tyrosine kinase that mediates essential signaling events in both innate and adaptive immunity downstream of the type I and II interferon (IFN) receptors (PMID: 7615558, 16239216, 28111307, 32750333), as well as IL-2 and IL-10 receptors (PMID: 11909529, 12133952). After receptor-ligand binding, JAKs phosphorylate specific tyrosine residues on each receptor subunit’s cytoplasmic tail, creating docking sites for STAT recruitment and phosphorylation. The phosphorylated STATs then homo- or hetero-dimerize and translocate to the nucleus to activate gene transcription. For example, signaling through the IL-2 receptor complex leads to JAK1/3-dependent STAT5A/B recruitment and activation. While JAK1 can directly phosphorylate STAT proteins, it can activate STAT signaling through the transactivation of other receptor-associated JAK kinases (PMID: 16239216, 32750333).

Eletto et al. (2016) identified 2 homozygous variants (P733L and P832S) in a patient with recurrent atypical mycobacterial infections and early-onset metastatic bladder cancer (PMID: 28008925). Patient cells showed reduced JAK1 and STAT phosphorylation, as well as target gene expression, in response to cytokine stimulation, suggesting a LOF effect. Reconstitution experiments suggested that the P733L variant made the more significant phenotypic contribution. Del Bel et al. (2017) subsequently ide ntified a heterozygous GOF variant (A634D) in 3 members of a family with autoinflammation, immune dysregulation, and eosinophilia (AIIDE) [OMIM: 618999]. Immortalized patient B cells showed enhanced baseline and post-stimulation pSTAT1, while primary T cells showed increased pSTAT3 in response to IL-6 (PMID: 28111307). Ruxolitinib treatment attenuated the patients’ cellular features of hyperactive JAK/STAT signaling and their clinical symptoms. Gruber et al. (2020) identified another GOF variant (S703I) in a patient with autoinflammatory and atopic disease, eosinophilia, and refractory membranous nephropathy (PMID: 32750333). Interestingly, this mutation not only increased JAK1 activity, but it also transactivated partnering JAKs independently of the catalytic domain, enabling STAT-dependent signaling cascades not canonically mediated by JAK1. Takeichi et al. (2022) reported a heterozygous variant (H596D) in a patient with AIIDE-like features (failure-to-thrive, eosinophilia, atopic dermatitis, and hepatosplenomegaly), but also autism, significant hyperkeratosis, and early-onset hepatitis developing into cirrhosis but without significant GI or renal involvement. Knock-in mice showed upregulation of genes associated with JAK/STAT and NF-κB hyperactivation and a 22q11-like transcriptomic signature that may contribute to the autism phenotype. At ESID 2024, Marie Jeanpierre et al. reported characterization of 5 novel monoallelic JAK1 variants (see AIIDE entry for further details) [Load More]