Model for the roles of TpoR Y112 and Y78 in pathologic signaling by TpoR W515 mutants. The wild-type TpoR (TpoRwt) contains a juxtamembrane domain K(R)WQFP that maintains the unliganded receptor inactive. TpoRwt is activated upon Tpo stimulation leading to conformational change of the receptor and to activation of major signaling pathways. In the absence of the K(R)WQFP juxtamembrane motif (Δ5TpoR), or in situations where the W515 of this motif is substituted by other residues (ie, W515A), the receptor assumes an active dimeric conformation, which activates JAK2 in a ligand-independent manner. Y78 plays a negative role in signaling through TpoRwt or the active TpoR. Mutation of Y78 into phenylalanine in the context of the activating W515 mutations led to strong pathologic signaling and myelofibrosis. In contrast, the TpoR-Y112F mutation decreases signaling of the receptor and abolishes the myeloproliferative and myelofibrosis phenotype.