JAK2 structure and function. JAK2, a ubiquitously expressed member of the Janus family of non-receptor tyrosine kinases, plays a key role in cytokine receptor signaling. It is involved in the control of cellular growth and proliferation, as occurs during bone marrow hematopoiesis. Top, Like all JAK proteins (there are four mammalian members of the Jak family), JAK2 possesses four structural domains: 1) an N-terminal FERM domain, 2) an SH2-like (SH2L) domain, 3) a kinase-like or pseudokinase domain [JH2 (Janus homology-2)], 4) and a C-terminal tyrosine kinase domain (JH1). Receptor binding and specificity are determined solely by the FERM and SH2L domains of JAKs. Bottom, Under normal conditions, binding of erythropoietin to the erythropoietin receptor (EPOR) induces conformational changes in the receptor that result in the activation of receptor-associated JAK2 molecules and the phosphorylation of specific tyrosine residues within the intracellular domain of the cognate receptor. Upon recruitment to the receptor, downstream signaling proteins are phosphorylated by JAK kinases, leading to their activation. In this way, extracellular signals can be transmitted via receptor proximal events into the activation of multiple downstream effector processes, including STAT transcription factors, the Ras/MAPK pathway, and the PI3K/AKT pathway. The V617F mutation results in a constitutively active JAK2 molecule. Learn more here.
