Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

JAK2 (O60674) - Overview - Molecular Target Synopsis

Protein


JAK2, Tyrosine-protein kinase JAK2
Enzyme Classification 2.7.10.2
UniProt O60674

Also Known as JAK2_HUMAN, JAK2

Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins (PubMed:7615558). Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins (PubMed:9618263). Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. Part of a signaling cascade that is activated by increased cellular retinol and that leads to the activation of STAT5 (STAT5A or STAT5B) (PubMed:21368206). In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation (PubMed:20098430). Plays a role in cell cycle by phosphorylating CDKN1B (PubMed:21423214). Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin (PubMed:19783980). Interacts with EPOR, LYN, SIRPA, SH2B1 and TEC (By similarity). Interacts with IL23R (PubMed:12023369). Interacts with SKB1 (PubMed:10531356). Interacts with STAM2 (PubMed:10899310). Interacts with IFNGR2 (via intracellular domain) (PubMed:7673114, PubMed:7615558). Interacts with LEPR (Isoform B) (By similarity). Interacts with HSP90AB1; promotes functional activation in a heat shock-dependent manner (PubMed:20353823). Interacts with STRA6 (PubMed:21368206). Interacts with RHEX; this interaction occurs in a erythropoietin (EPO)-dependent manner (PubMed:25092874).

6M9H
JAK2 JH2 IN COMPLEX WITH DIAMINOPYRIMIDINE JAK040
RCSB/PDB
Inspect Structure
See all 3D Structures for JAK2

Isoforms / Transcripts (Protein Coding)


Protein Length Ensembl Gene Ensembl Transcript Ensembl Protein Uniprot Isoform
1132ENSG00000096968ENST00000539801, ENST00000381652ENSP00000440387, ENSP00000371067O60674-1
983ENSG00000096968ENST00000544510ENSP00000443103

Drugs


JAK2 is targeted by Approved Drugs Baricitinib, Ruxolitinib. (see details)
Baricitinib
Ruxolitinib

Sub-cellular localization


UniProt: JAK2 is active in the following subcellular-locations: cytoplasm, endomembrane system, nucleus.
GO terms: JAK2 is active in the following subcellular-locations: caveola, cytoplasm, cytoskeleton, cytosol, endosome lumen, focal adhesion, glutamatergic synapse, membrane raft, nuclear matrix, nucleoplasm, nucleus, plasma membrane, postsynapse.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project JAK2 has gain in 8 cell-lines, loss in 12 cell-lines and no signal in 985 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: K_562, MCF7, SK_OV_3

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: OCI-M1, HEL, SET-2

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: K562, GM12878, CD14-positive monocyte

(see details)

RNA Interference


JAK2 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: SIHA, SCC90. (see details)

3D Structures


For JAK2 there are:
86 structures (137 chains) solved
82 are solved in complex with at least one small molecule ligand
1 are solved with an approved drug

JAK2 is solved in complex with the approved drug(s):

MI1/TOFACITINIB (3FUP_A, 3FUP_B).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


JAK2 has been screened with 4510 compounds (5996 bioactivities), 2478 compounds have bioactivities that show binding affinity of <= 500nM (2905 bioactivities). (see details)