JAK/STAT Signaling - Liver Cancer
The JAK (Janus kinase) / STAT (signal transducer and activator of transcription) signaling pathway transduce signals that are essential for development, cellular differentiation and homeostasis. This pathway plays a critical role in cytokine receptor systems, regulating growth, survival and pathogen resistance. JAK is a family of non-receptor protein tyrosine kinases, consisting of JAK1, JAK2, JAK3 and TYK2 (Tyrosine Kinase-2). STATs are transcription factors that activated following recruitment to an activated receptor complex, seven STAT proteins have been identified: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6.
Various ligands including cytokines (e.g. interferons and interleukins), hormones (e.g. erythropoietin and growth hormone) and their cell surface receptors activate JAK proteins, which autophosphorylate, and then phosphorylate the receptor. Subsequently, JAKs phosphorylate a specific tyrosine residue on the STAT protein, promoting dimerization via SH2 domains. The activated STATs form homo-/heterodimers and translocate to the nucleus to trigger target gene transcription. In addition, suppressors of cytokine signaling (SOCS) family inhibit receptor signaling via homologous or heterologous feedback regulation. Dysregulation in JAK/STAT signaling is associated with diseases such as atherosclerosis, immunodeficiencies and cancer.
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Gefitinib, also known as ZD1839 or Iressa, is a potent and orally-bioavailable small-molecule inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase with 50% inhibition concentration IC50 values of 0.033 μM and 0.027 μM in A431 membrane prep and baculovirus lysate respectively.