Open reading frame 36 (ORF36) of Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a serine/threonine-type viral protein kinase (vPK). Previous studies have examined the functions of KSHV vPK; however, its role in the activation of extracellular signal-regulated kinase (ERK1/2) has not yet been described to date. Using HEK 293 cell lines, we performed a human phospho-kinase array analysis to screen for MAPK signaling pathways kinases that are activated by KSHV vPK. In addition, we investigated the regulator protein phosphorylation of up/downstream ERK1/2 pathway; nuclear translocation of phosphorylated ERK1/2; and regulation of transcription factor, inflammatory cytokine, and pro-/antiapoptotic factor by KSHV vPK transfection. Here, we demonstrated that KSHV vPK activates ERK1/2 signaling pathway and plays an important role in the activation of MAPK/ERK signaling pathway. (C) 2019 Elsevier Inc. All rights reserved.