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, beta-catenin, hypoxia-inducible factor 1alpha and the homeobox proteins HOXB4 and HOXA9, and a number that are reduced, including glycogen synthase kinase 3alpha 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.
Kaushansky
K
K
Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0671, USA. kkaushansky@ucsd.edu
D006410:Hematopoiesis; D006801:Humans; D009369:Neoplasms; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction; D013926:Thrombopoietin / Q000378:metabolism*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D013926:Thrombopoietin