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“Neuroinflammation in Parkinson’s disease

MPN-restricted mutations activate JAK2 kinase–dependent cytokine receptor pathways

JAK2 is a member of the JAK family characterized by 2 kinase domains: 1 catalytically active at the C terminus and 1 catalytically inactive (or very weak) pseudokinase that prevents self-activation of the kinase domain.39 At the N terminus, JAKs possess a four-point-one ezrin radixin moesin (FERM)-like domain and a SH2-like domain. The noncovalent attachment of JAKs to cytokine receptors depends on the FERM domain. The JAK family kinases can be considered as the catalytic part of the hematopoietic cytokine receptor family as they are constitutively bound to the receptors intracellularly. In addition, the association of JAKs with receptors is important for their proper trafficking to the cell surface. Homodimeric receptors such as erythropoietin (EPO) receptor (EPOR), MPL, and granulocyte colony-stimulating factor receptor (G-CSFR) use JAK2, whereas heteromeric receptors use JAK1 and JAK2/tyrosine kinase 2 (TYK2) or JAK3. Cytokine binding induces changes in the conformation of receptors, which activate the JAKs bound to the receptor by trans-phosphorylation. The activated JAKs will phosphorylate the receptors, which are subsequently used as a docking site for other signaling molecules, more particularly the STATs. In the canonical pathway, STATs are phosphorylated by the JAKs, which induce their homodimerization or heterodimerization and subsequent trafficking to the nucleus where they regulate transcription of their target gene