JAK2 governs Transferrin Receptor 1 dynamics in mammalian cells

The dysregulation of the JAK/STAT signalling pathway is implicated in various human cancers, influence cell proliferation, survival, and tumour development. Activating mutations in the JAK2 kinase have been linked with myeloproliferative neoplasms (MPNs), particularly polycythemia vera (PV), characterised by increased red blood cell mass in the bone marrow. The advent of JAK2 inhibitors, exemplified by Ruxolitinib, has revolutionized personalized therapies for these conditions. Here, we explore the interplay between JAK2 and TfR1 (Transferrin Receptor 1). Our findings reveal that the kinase-dependent activity of JAK2 governs the steady-state levels and surface expression of TfR1, and its absence, resulting in decreased TfR1 abundance and a reduced endocytic rate of transferrin. Similarly, treatment of cells with the JAK2 inhibitor Ruxolitinib decreases TfR1 levels. Importantly, our co-immunoprecipitation analysis indicates that the N-terminal domain of JAK2 directly interacts with TfR1. Interestingly, JAK2 activating mutations, particularly the V617F mutation, enhance TfR1 protein stability and surface expression. Our data, therefore, elucidate the regulatory role of the N-terminus and kinase domains of JAK2 in controlling TfR1 stability, surface expression, and endocytic fate. Future research should explore the intricate link between JAK2 activity and TfR1-dependent iron regulation in cells.