K15 Protein of Kaposi's Sarcoma Herpesviruses Increases Endothelial Cell Proliferation and Migration through Store-Operated Calcium Entry.

Kaposi's sarcoma (KS) is a tumor of the vascular endothelium that is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). K15 of KSHV is a specific gene encoding a transmembrane protein. Two highly different forms of K15, the predominant (K15P) and minor (K15M) have been identified in different KSHV strains. In genomic locations and protein topology, two K15 alleles resemble the latent membrane protein (LMP) 1 and LMP2A of Epstein⁻Barr virus. Both K15 proteins have motifs similar to those found in LMP1 and LMP2A. K15 therefore seems to be a hybrid of a distant evolutionary relative of LMP1 and LMP2A. Ca is a second messenger and participates in numerous activities in cells, like proliferation, migration and metastasis. It has been found previously that LMP1 increased Ca influx through store-operated calcium channels and blockade of LMP1 reduced store-operated Ca entry (SOCE). LMP2A has similar activity. So we sought to determine whether K15 had similar activity. We showed that K15P induced Ca influx and enhanced expression of Orail1, which is a vital protein in SOCE, and overexpression of K15P improved cell motility. Mutant K15P did not show these activities in HEK-293T and EA.hy 926 cells. Our results showed that K15P increased cell proliferation and migration though SOCE and established a novel mechanism for the development of KS and KSHV-associated diseases.