Molecular mechanisms of thrombopoietin signaling

The molecular pathways that regulate thrombopoiesis are becoming increasingly understood. Upon binding to its receptor, the product of the c‐Mpl proto‐oncogene, thrombopoietin activates a number of secondary messengers that promote cell survival, proliferation and differentiation. Amongst the best studied are the signal transducers and activators of transcription, phosphoinositol‐3‐kinase, and the mitogen‐activated protein kinases. Additional signals activated by these secondary mediators include mammalian target of rapamycin, β‐catenin, hypoxia‐inducible factor 1α and the homeobox proteins HOXB4 and HOXA9, and a number that are reduced, including glycogen synthase kinase 3α and the FOXO3 family of forkhead proteins. More recently, a number of signaling pathways have been identified that turn the thrombopoietin signal off, a step necessary to avoid uncontrolled myeloproliferation, and include the phosphatases PTEN, SHP1 and SHIP1, the suppressors of cytokine signaling, and down‐modulation of surface expression of c‐Mpl. This review will focus on these pathways in normal and neoplastic hematopoiesis.