Abstract
Mutant calreticulin promotes transport of defective TPOR proteins to the plasma membrane.
Major finding: Mutant calreticulin promotes transport of defective TPOR proteins to the plasma membrane.
Concept: The rogue chaperone activity of mutant calreticulin is required for oncogenic transformation.
Impact: Targeting mutant calreticulin may prevent pathologic TPOR activation at the cell surface.
Somatic frameshift mutations in calreticulin (CALR), which encodes a calcium-binding chaperone protein that regulates protein folding quality control in the endoplasmic reticulum (ER), occur in approximately 20% to 30% of patients with essential thrombocythemia and primary myelofibrosis, two types of myeloproliferative neoplasms (MPN). These mutations eliminate the ER retention signal and create a mutant-specific positively charged C-terminal tail that interacts with the thrombopoietin receptor (TPOR). Although it is known that this new C-terminus and TPOR activation are both required for oncogenic transformation by mutant CALR, the exact function of the mutant CALR protein remains unclear. Pecquet, Chachoua, Roy, Balligand, and colleagues observed that mutant CALR and TPOR colocalize outside of the ER in the Golgi network compartments and at the plasma membrane, and that the ER-to-Golgi secretory pathway is required for activation of TPOR by mutant CALR. Mutant CALR bound directly to TPOR and enhanced its stability and promoted its dimerization and localization to the plasma membrane, where it was activated in a TPO-independent manner and induced downstream JAK–STAT signaling. Mutant CALR also could promote cell-surface trafficking of immature, folding-deficient, or trafficking-impaired mutant or ER-retained TPOR protein, suggesting that MPN-associated CALR mutations endow the mutant CALR protein with rogue chaperone activity that facilitates cytokine-independent activation of TPOR at the cell surface. Furthermore, TPOR cell-surface localization was a requirement for oncogenic transformation by CALR mutants. These findings establish the functional consequences of the CALR mutations identified in MPN and suggest that strategies to target mutant CALR may prevent cytokine-independent TPOR activation and proliferation in MPN.
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