Calreticulin-From the Endoplasmic Reticulum to the Plasma Membrane-Adventures of a Wandering Protein.

Calreticulin (CRT) is a 46 kDa highly conserved protein initially identified as calregulin, a prominent Ca-binding protein of the endoplasmic reticulum (ER). Subsequent studies have established that CRT functions in the ER's protein folding response and Ca homeostatic mechanisms. An ER retention signal on the carboxyl terminus of CRT suggested that CRT was restricted to the ER. However, the identification of CRT in the nucleus and cytosol has established that CRT is a multi-compartmental, multifunctional protein. CRT also plays an important role in cancer progression. Most recently, CRT was identified on the cell surface and shown to be a potent 'eat-me' signal that plays a key role in the uptake of apoptotic and viable cancer cells by phagocytes. Elevated CRT exposure on the outer leaflet of cancer cells has been linked with anticancer immunity and superior therapeutic outcomes in patients with non-small cell lung carcinoma, colorectal carcinoma, acute myeloid leukemia, ovarian cancer, and high-grade serous carcinomas. Mutations in the CRT gene have been identified in a subset of patients with myeloproliferative neoplasms. The most recent studies from our laboratory have revealed a new and significant function for extracellular CRT as a plasminogen receptor. This discovery has profound implications for our understanding of the role of CRT in myeloproliferative neoplasms, specifically, essential thrombocythemia.