Figure 1.
Overview of JAK activation and regulation. (A) Summary of the JAK/STAT signalling pathway and its negative regulation. Ligation of a cytokine receptor leads to a transition of the associated JAK molecules from an inactive (left) to activated state (middle). Activated JAK is characterised by phosphorylation of activation loop residues within its kinase domain (encircled P; middle). Activated JAKs phosphorylate tyrosines within the receptor intracellular region to enable recruitment and phosphorylation of the principal downstream effectors, the STATs. Many layers of negative regulation have been identified (right), including phosphatases (CD45, PTP1B, SHP1 and SHP2) and SH2 domain containing regulators from the LNK and SOCS families. SOCS proteins inhibit JAK signalling by both inhibiting kinase activity and by mediating ubiquitylation (encircled U), leading to proteasomal degradation.
(B) Intrinsic regulatory events annotated on the human JAK2 domain structure. Mutational hotspots associated with myeloproliferative neoplasms are annotated above [36, 37, 39, 41–49, 142, 143]. Residues subject to phosphorylation [65, 144–152] and sumoylation [153] are annotated below in black text and blue boxed text, respectively. In addition to the crucial role of the activation loop tyrosines, 1007 and 1008 [65, 66], Y119, Y221, Y317, Y570, Y637, Y813, Y866, Y913, Y966 and Y972 have been reported to arise from JAK2 auto- or trans-phosphorylation and contribute variously to the modulation of JAK2 activation [146–148, 150, 154–156].