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Effective communication between cells is significant to development, tissue and organism homeostasis, and host defense. Evolution has provided many elegant solutions to this problem, but among these the JAK-STAT pathway is one of the architecturally simplest paradigms, allowing direct communication from transmembrane receptors to the nucleus (Figure 1). JAK/STAT pathway is a relatively simple conserved reaction cascade involved in signal transduction in metazoans. After the ligand is bound, receptors dimerize and activate the associated Janus kinase (JAK) molecules. In some receptors, such as the insulin receptor or epidermic growth factor receptor, the cytoplasmic domain possesses tyrosine kinase activity of its own. Ligand binding causes autophosphorylation of receptor-bound JAKs, which increases their catalytic activity. JAKs also phosphorylate tyrosine residues of receptor subunits. Next, JAK-receptor complexes phosphorylate their major targets, signal transducer and activator of transcription (STAT) factors. Phosphorylated STAT molecules also dimerize and are transported in the nucleus, where they bind to specific regulatory sequences and induce the transcription of their target genes.
Figure 1. The JAK/STAT signaling pathway.
Abnormal activation of JAK/STAT signaling through JAK mutations or constitutive TYK2 signaling was shown to be important for the induction of aberrant hematopoietic stem cell development, hematological malignancies, autoimmunity and certain immunodeficiency syndromes. In that regard, inhibitors of JAK activation altered the natural killer cell, T-cell and DC activity, all of which are pertinent to the pathogenesis and progression of autoimmune disorders. More importantly, pharmacological inhibition of JAKs was shown to efficiently block the downstream events associated with type I/II cytokines and JAK SMIs have become useful as potent and efficacious medical therapies for a host of autoimmune diseases, such as psoriasis and inflammatory bowel diseases.
Constitutive activation of JAKs and STATs was first recognized as being associated with malignancy in the 1990s. The JAK-STAT pathway can be activated by multiple mechanisms, including activating mutations of receptors, autocrine/paracrine cytokine production, JAKs or other upstream oncogenes that in turn activate STATs, and activating mutations of STATs themselves. Somatic JAK2 mutations have been linked to many hematologic malignancies, and a cohort study indicated that the V617F mutation was associated with increased mortality in the general population. JAK3 mutations have been associated with lymphoma and leukemia. Secondary mutations in JAK3 have been described in juvenile myelomonocytic leukemia and are thought to be associated with disease progression. Aberrant activation of STATs has been found in a number of tumors. STAT3 is constitutively activated in solid and hematologic cancers, and cytokines produced by T cells can activate STAT3 in cancer cells to affect stemness and tumorigenicity. STAT3 has also been involved in the pathogenesis of diffuse large B cell lymphoma and solid-organ malignancies such as breast and nasopharyngeal carcinomas.
The discovery of the JAK-STAT pathway and its role in health and disease represents one of the most exciting developments in modern medicine and now acts as a paradigm for cell signaling and translational science. Basic molecular strategies together with genetic and phenotypic analysis have led to better immunopathogenic insights, diagnostic advances, and new therapeutic options for both common and rare diseases. Creative Biogene is able to offer a variety of JAK/STAT signaling pathway related products including stable cell lines, viral particles and clones for your drug discovery projects.
JAK/STAT Signaling Pathway Product Panel
| AKT1 | AKT2 | BCL2 | CCND1 | CCND3 | CDKN1A |
| EP300 | GRB2 | IFNAR1 | IFNGR1 | IL20 | IL6ST |
| IRF9 | MCL1 | MTOR | MYC | OSMR | PIAS1 |
| PIK3R1 | PIK3R2 | PIK3R3 | PTPN11 | RAF1 | STAT2 |
| STAT3 | STAT5B | STAT6 | TYK2 | CCND1 | CDKN1A |
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