JAk stands for Janus kinase and the STAT for signal transducers and activator of transcription (JAK/STAT).
In mammals, the JAK/STAT pathway is the fundamental signaling mechanism for a big selection of cytokines and growth factors.
JAK-STAT signaling Pathway Mechanism
The tyrosine kinase activity of Janus kinase is activated when the regulatory molecule binds and brings two receptor molecules together to form the dimer. Receptor dimerization brings the two JAKs into proximity, where they can phosphorylate each other. Phosphorylation further activates JAK, allowing it to phosphorylate the receptor.
The tyrosine kinase interest of JAK is activated simultaneously as the regulatory molecule binds and brings receptor molecules collectively to form a dimer. Receptor dimerization brings the two JAKs into proximity, wherein they could phosphorylate every other. Phosphorylation similarly turns on JAK, allowing it to phosphorylate the receptor.
The phosphotyrosine residues at the receptor proteins are binding sites for STAT proteins. The STAT proteins are taken into consideration as latent transcription factors. “Latent” means they are always present in the cytoplasm but are programmed to be activated using JAK.
STAT binds to the receptor, which brings it right into a role where it may be phosphorylated with the resource of JAK. Once phosphorylated, STATs can then shape a STAT dimer (every STAT molecule binds to the phosphotyrosine of the other phosphorylated STAT). The STAT dimer is a vital transcription issue.
It travels to the nucleus, in which it binds to unique sequences inside the DNA. Inactivation takes vicinity while phosphatases cast-off phosphate groups from various proteins within the signaling pathway.
List of cytokines acting through JAK-STAT
Cytokines are an important defense component of body innate immunity.
IFN-gamma: This comes under the category of cytokines, which activates the macrophage in a disease condition
IFN-alpha, IFN-beta: These cytokines are activated mainly in the case of viral infections and have an antiviral effect of limiting the spread and growth of the virus.
IL-2: This cytokine responsible for the proliferation of lymphocytes in the immune response pattern.
Drug acting on the JAK-STAT pathway
JAK inhibitors are the drugs that hinder the kinase activity of JAK. There are two drugs approved by the FDA.
Ruxolitinib has been approved to treat a myeloproliferative disorder.
Tofacitinib is one of the JAK inhibitors that has been approved for the treatment of rheumatoid arthritis.
In this area, several cytokines also exert their effects through JAK/STAT signal transduction pathway on the body. This happens due to its medical relevance to the tissues of the body. In this way, the cytokines are being exploited to perform the drug activation. They are either used as directly or indirectly, making it an effective therapy for curing several serious diseases. The cytokines can be used here as antagonists also. The delineation of the signal pathways has led to more good design assays of the chemicals used in this process.
The pharmaceuticals which act on the JAK-STAT pathways are of a broad protein nature like cytokines or other chemicals. Sometimes, they hinder the pathway process, but they are extensively used as therapeutics for treating deadly diseases.
JAK-STAT signaling pathway in Cancer
Cancer disease is well progressed through JAK-STAT signaling pathways. It helps in the progression of tumor cells in the body by acting as an intrinsic driver for it. The cancer growth or metastasis happens due to the intervention of the JAK-STAT signaling pathway. This special effect has paved the way for the determination of different types of cancers in the animal or human body.
The cause of the Constitutive activation of the JAK-STAT signaling pathway can arise from different mechanisms, which include elevation of cytokines. The most common cytokines in this range are upregulated interleukin (IL)-6, which signals through the classic mechanism. This mechanism is restricted by cell-type-specific expression of IL-6 receptor –alpha. It further engages with the expressed beta-subunit receptor of GP130. This results in the increased activity of the Janus kinase (JAK) signal pathway that mediates activation of an oncogenic transcription factor, signal activator, and transducer of transcription process (STAT) 3.
These activating mutations in GP130 result in ligand-independent activations of STAT3 in liver cancers. Like this, several cancer types are reported in humans due to the activation of JAK-STAT pathways. All mutations are based on their structural frameworks and consequences and biological activity, with oncogenic mutations in acute lymphoblastic leukemia.
With the JAK-STAT signaling pathway, the cancer types can be determined through the cytokines activated mutations to the genes cancer-causing pathogens.
JAK-STAT signaling in diabetic nephropathy
The excessive cellular growth counts for significant pathological changes in diabetic nephropathy. It is seen that high glucose-induced growth of glomerular mesangial cells leads to diabetic nephropathy. The glomerular mesangial cells respond to all traditional growth factors in an environment enriched with vasoactive mediators and high levels of glucose.
The pathway related to ANG-II is seen to implicate the pathogenesis of the diabetic renal disease. This activates the pathways of JAK-STAT signaling pathways along with reactive oxygen species. JAK-STAT pathway cascade gets activated in the respective glomerular mesangial cells. And due to this activation of the JAK-STAT pathway, there are stimuli for the excessive proliferation of glomerular cells with rapid growth. Glomerular cells of mesangial have both mitogenic and contractile properties that directly contribute to the physiological regulation of all glomerular dynamics. All this contributes to diabetic nephropathy in microenvironments, termed usually as high glucose level.
JAK-STAT pathway is an essential part of the physiological processes in animals and mammals. it affects nearly all important processes in direct or indirect ways. The pathway affects cancer-forming tumor cells by inhibiting them. It also affects diabetes neuropathy. Thus, JAK-STAT signaling is an essential part of it.