Mechanistic Study of Activation of Normal and Pathogenic Janus Kinase 2 and Their Associations with the Erythropoietin Receptor

A point mutation in the Janus kinase 2 (JAK2) pseudo-kinase domain, V617F, is found in most patients with Polycythemia Vera and those with other myeloproliferative disorders. This mutation enables cytokine-independent activation of JAK2 in cells that express a homodimeric cytokine receptor such as the erythropoietin receptor (EpoR). The activation mechanisms of both normal and pathogenic JAK2 are poorly understood. Jiahai Shi is studying the interaction between JAK2 and the EpoR cytoplasmic domain by X-ray crystallography. In particular he will determine the binding interface between the EpoR BOX 1 motif and JAK2 FERM domain. This interface would be a novel and specific drug target against JAK2-V617F positive myeloproliferative disorders.