JAK Inhibitors

The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling pathway play an important role in cell proliferation, cell differentiation, cell migration, and cell death. It is the principal signaling mechanism for a variety of cytokines and growth factors. Constitutive activation or dysregulation of JAK/STAT signaling can result in inflammatory disease, erythrocytosis, gigantism, and leukemia.

In the JAK/STAT signaling scheme, ligand binding to cytokine receptors induces dimerization of their receptor subunits. They may either form homodimers, as in case of erythropoietin, or heterodimers as in case of interferons and interleukins. Following ligand binding, the cytoplasmic domains of two receptor subunits associate with JAK tyrosine kinases. In mammals, the JAK family is composed of four members: JAK1, JAK2, JAK 3, and Tyk2. Ligand binding brings the two JAKs into close proximity, allowing their transphosphorylation. The activated JAKs can then phosphorylate STATs. In mammalian cells seven different STATs been recognized. They contain a conserved tyrosine residue near the C-terminus, which is phosphorylated by JAKs. This tyrosine phosphorylation allows the dimerization of STATs by interacting with a conserved SH2 domain. In their latent form STATs are located in the cytoplasm and upon phosphorylation they are transported into the nucleus by an importin a-5 dependent mechanism. In the nucleus, dimerized STATs bind to specific regulatory sequences to activate or repress transcription of target genes.

JAK/STAT signaling is negatively regulated by three different mechanisms. They include suppressors of cytokine signaling (SOCS), protein inhibitors of activated stats (PIAS) and protein tyrosine phosphatases (PTPs). SOCS proteins contain an SH2 domain and a SOCS box at their C-terminus. They also contain a small kinase inhibitory domain located N-terminal to the SH2 domain. Activated STATs are reported to stimulate transcription of the SOCS genes and the resulting SOCS proteins bind to phosphorylated JAKs and block their activity. The SOCS can also bind to phosphotyrosines residues on the receptors and block the recruitment of STATs to these receptors. The PIAS protein family consists of five members: PIAS1, PIAS3, PIASxa, PIASxb, and PIASy. They bind to activated STAT dimers and prevent their DNA binding. They contain a Zn-binding RINGfinger domain in their central domain, a well-conserved SAP (SAF-A/Acinus/PIAS) domain at the N-terminus, and a lesswell- conserved carboxyl domain. SHP-1, a tyrosine phosphatase can also regulate JAK/STAT signaling by dephosphorylating JAK. Here, the SH2 domains of SHP-1 bind phosphorylated JAK and/or phosphorylated receptors to block JAK/STAT signaling.

JAK/STAT signaling pathways is also involved in cross talk between the receptor tyrosine kinase/ Ras/MAPK pathway at multiple levels. Activated JAKs can phosphorylate tyrosines on their associated receptors, which serve as docking sites for SH2-containing adapter proteins, such as SHP-2 and Shc, from other signaling pathways. JAK is also reported to phosphorylate insulin receptor substrate (IRS) and p85, which results in the activation of the phosphoinositide 3-kinase (PI 3-K) pathway.

JAK/STAT pathway is reported to play an important role in the establishment of cell fate. For example, IL-12 promotes differentiation of CD4+ T cells to Th1 cells by activating STAT4, and stat4 knockout mice fail to respond to IL-12 and produce only Th2 cells. On the other hand IL-4 activates STAT6 and promotes differentiation of CD4+ T cells to Th2 cells. JAK/STAT pathway is also involved in hematopoeitic development. Targeting of Jak2 gene is shown to result in embryonic lethality in mice due to failure of erythropoiesis. In addition, JAK/STAT pathways have been reported to be constitutively active in several forms of human cancers.

References:
Yu, H., et al. 2009. Nat. Rev. Cancer 9, 798.
Pfeifer, A.C., et al. 2008. Essays Biochem. 45, 109.
Rawlings, J.S. et al. 2004. J. Cell Sci. 117, 1281.
Shuai, K., and Liu, B. 2003. Nat. Rev. Immunol. 3, 900.
Hou, S.X. et al. 2002. Dev. Cell 3, 765.

Highlighted below are inhibitors included in InhibitorSelect™ JAK/STAT Signaling Pathway Inhibitor Panel (Cat. No. 420138).