Schematic representation of SOCE activation in physiologic and pathologic megakaryopoiesis. In physiologic conditions (A), upon binding with TPO, c-Mpl promotes phosphorylation of downstream signaling molecules (STAT, AKT, ERK) together with IP3 formation and consequent mobilization of the IP3-sensitive Ca²⁺ pool. In Mks with repleted ER, STIM is localized in an inactive configuration in the ER membrane, and forms a complex with CALR and ERp57. Depletion of Ca²⁺ stores triggers Ca²⁺ release from the ER through IP3 receptors (IP3Rs) and consequent Ca²⁺ dissociation from STIM-CALR-ERp57 complex. Consequently, STIMs oligomerize and translocate next to the plasma membrane. Then, STIM binding to Orai and TRPC results in the opening of these channels and extracellular Ca²⁺ entry. The increased cytosolic Ca²⁺ concentration ([Ca²⁺]_i) in turn sustains the long-lasting phosphorylation of c-Mpl downstream pathways. In pathologic conditions (B), the TPO-independent activation of c-Mpl by mutant CALR, which leaves the ER and consequently loses its binding to STIM and ERp57, leads to a constitutive activation of SOCE, which results in increased Mk proliferation.