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neuronal death and implications

Activation of MPL by TPO induces the activation of JAK2 and TYK2, which are constitutively bound to the receptor, but only the activation of JAK2 is indispensable for signaling and induction of proliferation by MPL. MPLW515 is located in the amphipathic domain of MPL, which prevents spontaneous activation of MPL.4All substitutions of W515, except W515C and W515P, will lead to the activation of MPL in the absence of TPO and will activate JAK2. The S505N mutation induces a stable active dimer. However, both types of mutations activate constitutive signaling through induction of productive dimerization of the transmembrane helix of MPL.20,25

CALR in contrast is not a signaling molecule, but an ER chaperone involved in the quality control of N-glycosylated proteins and in calcium storage. The initial publication on CALR mutations has shown that CALRdel52 was able to activate STAT5 and this was impeded by JAK2 inhibition.2Recent studies have established that CALR mutants can activate MPL and subsequently JAK2Mutant CALR requires both its mutant C terminus and MPL for oncogenic transformationWT CALR and mutant CALR bind to the N-glycosylated residue of the extracellular domain of MPL in the ER, and the lectin-binding activity of CALR mutants as well as the new tail are required for MPL activation. This binding is reinforced by the new C terminus and its positive charges, which lead to activation of the receptor.It is unknown at which cellular compartment MPL is activated, but there is evidence that CALR mutants behave as an abnormal chaperone and traffics with MPL to the cell surface. In this case, MPL activation can occur anywhere from the ER to the cell surface. Moreover, CALR mutants are secreted and may induce cytokine secretion by monocytes.CALR mutants also appear to slightly activate the G-CSFR, but not the other cytokine receptors.Whether this activation of G-CSFR plays a role in the pathogenesis of mutant CALR+MPN is unknown