Thrombopoietin receptor : regulation, dimerization, oncogenic activation and bimodal signaling

Abstract

Philadelphia negative myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia and primary myelofibrosis. Those MPNs are clonal diseases for which the phenotype is almost always driven by exon-specific somatic mutations in three genes: JAK2 exon 14, MPL exon 10 and CALR exon 9. MPL/TpoR is a homodimeric receptor that is a central player for developing a full JAK2 V617F or CALR mutant disease in mice. However, the receptor itself can suffer from pathological activating and dimerizing mutations within exon 10, namely W515X and S505N. This thesis addresses TpoR physiologic and oncogenic activation, dimerization and orientation dependent signaling including dimeric interfaces and transmembrane domain tilt angle. This thesis explains also transmembrane and juxtamembrane regulation mechanisms that are sometimes human specific and that prevent activation of a receptor otherwise primed for activation.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201