Key JAK-STAT Pathway Targets
Four JAK family kinases, including JAK1, JAK2, JAK3, and TYK2, and seven STAT family members, including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6, have been identified. JAK1, JAK2, and TYK2 appear to be ubiquitously expressed, while JAK3 expression is normally limited to lymphoid cells. The JAKs are structurally unique in having a C-terminal kinase domain (JH1) preceded by a pseudokinase domain (JH2), which lacks the catalytic activity but has a critical regulatory function. JAKs also have a Src homology 2 (SH2) domain and an N-terminal band four-point-one, ezrin, radixin, moesin (FERM) domain that is critical for mediating the association with cytokine receptors. STAT proteins contain a SH2 domain for dimerization and a DNA-binding domain. The amino acid sequence diversity and their tissue-specific distributions account for the diverse roles of STATs in response to extracellular cytokines.1-2 The JAK-STAT pathways are up-regulated by a vast array of cytokines/growth factors. One mechanism for negative regulation of JAK-STAT pathways is through suppresser of cytokine signaling (SOCS) proteins, which directly bind to and inactivate JAKs3, and protein inhibitors of activated STATs (PIAS) that bind to phosphorylated STAT dimers, preventing DNA binding.4
Abnormal constitutive activation of JAK-STAT pathways has been implicated in various cancers and immune disorders. For example, STAT3 is persistently activated in many tumors, including major carcinomas and some hematologic tumors.5 Activating mutations in JAK2 have been linked to leukemia. TEL-JAK2 fusion due to chromosomal translocation was identified in a small set of human T cell acute lymphoblast leukemia patients.6 The V617F mutation in the JH2 pseudo-kinase domain of JAK2 was found in a high percentage of patients with myeloproliferative disorders, including polycythaemia vera.7 Inhibitors of JAK-STAT pathways are currently being sought in the areas of oncology and immune disorders.
Events leading to STAT activation.
|KPNA1 (NPI-1)||RELA (NFκB)||SUMO1|
|ALK||F2R (Par1)||KDR (CD309)|
|AXL (UFO)||F2RL2||KIT (CD117)|
|CD4||FGFR3 (CD333)||MST1R (CD136)|
|CSF1R (CD115)||FLT1||NGFR (CD27)1|
|CXCR4 (CD184)||FLT3 (CD135)||NTRK1|
|EPHA1||IFNAR2 (CD118)||PDGFRA (CD140a)|
|EPHA2||IFNGR1 (CD119)||PDGFRB (CD140b)|
|EPHA7||IL2RG (CD132)||TNFRSF10A (CD120a)|
|EPHA8||IL3RA (CD123)||TNFRSF10B (CD262)|
|EPHB1||IL4R (CD124)||TNFRSF1A (CD120a)|
|EPHB2||IL6R (CD126)||TNFRSF1B (CD120b)|
|ERBB2 (Her2)||INSR (CD220)|
|CCL21 (6Ckine)||IL1A||TNFSF10 (TRAIL)|
|CCL25 (TECK)||IL1B||TNFSF13B (BAFF)|
- Aaronson, D.S. et al. (2002) Science 296: 1653-1655.
- O’Shea, J.J. et al. (2004) Nat Rev Drug Discovery 3: 555-564.
- Kishimoto, T. et al. (2001) Nat Genetics 28: 4-5.
- Shuai, K. et al. (2000) Oncogene 19 : 2638-2645.
- Darnell, J.E. et al. (2005) Nat Medicine 11: 595-596.
- Lacronique, V. et al. (1997) Science 278: 1309-1312.
- Ferrajoli, A. et al. (2006) Curr Cancer Drug Targets 6: 671-679.
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