MPL expression and localization is modulated by wild-type or mutant JAK2 with differing consequences in low or high thrombopoietin concentrations. (A) In the context of JAK2^WT expression, the thrombopoietin receptor (MPL) is rendered resistant to endoglycosidase H–mediated degradation and is recycled back to the cell surface after ligand binding. At low levels of thrombopoietin (TPO), this TPO^low-MPL-JAK2^WT signaling cascade leads to growth and survival of cells. (B) When exposed to higher levels of TPO, cells expressing JAK2^WT will have high levels of MPL on the cell surface and this TPO^high-MPL-JAK2^WT signaling results in quiescence and apoptosis of cells. It is possible that high levels of TPO result in a signalosome that recruits additional cofactors, facilitating the switch from growth to quiescence/apoptosis. (C) In the context of JAK2^V617F, MPL is internalized, ubiquitinated, and undergoes proteosomal degradation. As a result, cell surface expression of MPL is much lower in cells with JAK2^V617F, facilitating resistance to the quiescence/apoptosis that would normally be encountered after exposure to high levels of TPO and allowing these cells to continue to proliferate. (D) In the presence of a JAK2 kinase inhibitor (or proteosome inhibitor), JAK2^V617F is no longer capable of inducing internalization of MPL. Because MPL is still on the cell surface, exposure to high concentrations of TPO can once again induce quiescence/apoptosis of these neoplastic cells.