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Types of tyrosine kinases
There are two classes of tyrosine kinases; receptor tyrosine kinase and non-receptor cytoplasmic tyrosine kinase. The Janus Kinases (JAKs) are the non-receptor cytoplasmic tyrosine kinases that are associated with the cytokine receptors and participate in different downstream signaling pathways. Cytokine receptors are the cell surface receptor that binds to the different mediators and some hormones collectively called cytokines.
Cytokine receptor and activation of the JAKs
Cytokine receptors don’t possess any catalytic activity and, therefore, JAKs associated with it catalyze and activate the downstream signaling molecules. There are four mammalian JAKs; JAK1, JAK2, JAK3, and Tyk2 which are activated by different cytokine receptors.
Once cytokine binds to the cytokine receptor, conformational changes in the cytokine receptor lead to the activation of the JAKs. Activated JAK trans-phosphorylates the key tyrosine residue of the partner JAK on another receptor. Trans-phosphorylated JAKs phosphorylate the key tyrosine residues of the cytokine receptors that provide docking sites for the downstream signaling molecules “signal transducers and activators of transcription (STATs)”.
JAK-STAT downstream signaling
Once STATs bind to the cytokine receptor through their SH2 domain, JAKs phosphorylate the tyrosine residues of the STATs and cause dissociation of the STATs from the cytokine receptor and their dimerization. The phosphotyrosine residues of one STAT molecule interact with the SH2 domain of another STAT and vice versa forming dimer STATs complex.
JAK-STAT-regulated gene expression
STATs dimer molecules are translocated into the nucleus where they bind to the cytokine-responsive cis-regulatory element along with the co-transcription factors. genes mediated by the JAK-STAT signaling pathway are responsible for the different cellular processes such as cell proliferation and differentiation, T cell and B cell-mediated immunity.
However, JAK-STAT can be a target of different inhibitors such as arsenic that inhibits the JAK-STAT signaling pathway and leads to the alteration of the cell proliferation, differentiation, activation of apoptosis and immunotoxicity. Other inhibitors include inhibitors of the cytokine that may ultimately destabilize the cytokine receptor and inhibits the JAK-STAT pathway related to cellular processes.