The CALR mutants bind and activate MPL. (A) WT CALR binds to MPL in the ER by interaction of its lectin domain with MPL N-glycosylation, controls the quality of the proteins, and then comes away from the receptor, which traffics to the cell surface mainly by the conventional route to the cell surface. A completely glycosylated MPL (mature form) is expressed at the cell surface where it binds TPO to be activated. CALR mutants bind to MPL in the ER by the same interaction as the WT but the interaction is reinforced by the new C terminus. (B) The mutant CALR remains bound to MPL and probably traffics to the membrane both conventionally and unconventionally (autophagosomes and pre-Golgi) to the membrane. This leads to the presence of an immature MPL form on which the mutant CALR is bound. Activation of MPL is dependent on the new C terminus and also takes place on the membrane (Stefan Constantinescu, W.V., unpublished results). In cell lines, this leads to activation of mainly the STAT pathway whereas the extracellular signal-regulated kinase (ERK) is slightly activated and the PI3K pathway even less. In cell lines, MPL that binds mutant CALR can only be slightly activated by TPO. Professional illustration by Somersault18:24.