In cardiac and many other systems, chronic stress activates avfamily of structurally and functionally conserved receptors and their downstream signaling molecules that entail tyrosine, serine or threonine phosphorylation to transfer the messages to the genetic machinery. However, the activation of the Janus kinases (JAKs) and their downstream signal transducer and activator of transcription (ST...

A variety of cytokines activate receptor-associated members of the Janus family of protein tyrosine kinases (Jaks). To assess the role of Jak2, we have derived Jak2-deficient mice. The mutation causes an embryonic lethality due to the absence of definitive erythropoiesis. Fetal liver myeloid progenitors, although present based on the expression of lineage specific markers, fail to respond to er...

The SOCS1 functions downstream of cytokine receptors, and takes part in a negative feedback loop to attenuate cytokine signaling. The SOCS1 is rapidly induced following stimulation by several type I and type II cytokines, and it attenuates their signaling by its ability to bind and inhibit all four of the Janus family of intracellular tyrosine kinases (JAKs). The SOCS1 functions as a negative r...

Stimulation of CD95/Fas drives and maintains cancer stem cells (CSCs). We now report that this involves activation of signal transducer and activator of transcription 1 (STAT1) and induction of STAT1-regulated genes and that this process is inhibited by active caspases. STAT1 is enriched in CSCs in cancer cell lines, patient-derived human breast cancer, and CD95high-expressing glioblastoma neur...

Treatment of rheumatoid arthritis (RA) with biologic agents targeting inflammatory cytokines and cell surface molecules such as tumor necrosis factor and Interleukin-6 is generally more efficacious than traditional disease-modifying antirheumatic drugs when combined with MTX. However, not only do ~30% of patients poorly respond to treatment but also parenteral mode of administration and expense...

Acute atherosclerotic complications, such as myocardial infarction, are often provoked by the rupture of an atherosclerotic plaque and the subsequent thrombotic occlusion of the arterial lumen, which interrupts the blood flow and renders ischemic the downstream peripheral tissue. Several inflammatory mediators (including cytokines, chemokines and matrix metalloproteases) have been shown to orch...

Dysregulated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling due to activation of tyrosine kinases is a common feature of myeloid malignancies. Here we report the first human disease-related mutations in the adaptor protein LNK, a negative regulator of JAK-STAT signaling, in 2 patients with JAK2 V617F-negative myeloproliferative neoplasms (MPNs). One patient e...

Interferons (IFNs) induce early-response genes by stimulating Janus family (Jak) tyrosine kinases, leading to tyrosine phosphorylation of Stat transcription factors. Previous studies implicated protein-tyrosine phosphatase (PTP) activity in the control of IFN-regulated Jak/Stat signaling, but the specific PTPs responsible remained unidentified. We have found that SH2 domain-containing PTP1 (SHP...

Janus kinases (JAKs) have been known to play crucial roles in modulating a number of inflammatory and immune mediators. Here, we describe a series of 1H-pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting JAK3 for use in treating immune diseases such as organ transplantation. In the chemical modification of compound 6, the introduction of a carbamoyl group to the C5-position ...

Many studies have suggested that E3 ubiquitin ligases can behave as either oncogenes or tumour suppressor genes and, recently, it has become clear that the SOCS (suppressor of cytokine signalling) E3 ligases fit this mould. While most cancer-associated E3s regulate the cell cycle or DNA repair, the SOCS proteins inhibit growth factor responses by degrading signalling intermediates such as JAKs ...