YWK-II protein as a novel Go-coupled receptor for Mullerian inhibiting substance in cell survival

Mullerian inhibiting substance (MIS) has recently been implicated in multiple cellular functions including promotion of cell survival, but the receptor(s) and signaling pathways involved remain elusive. We have investigated the possibility of YWK-II protein, previously shown to interact physically with MIS and G(o) protein, being a receptor mediating the cell survival effect of MIS. In YWK-II-overexpressing CHO cells, MIS activates the G(o)-coupled ERK1/2 signaling pathway and promotes cell survival with altered levels of p53 and caspase-3. YWK-II antibody is found to interfere with the ability of MIS to promote viability of mouse sperm and affect MIS-activated ERK1/2 phosphorylation. In vivo studies involving injection of YWK-II antibody into the seminiferous tubule of the mouse testis, where MIS is known to be produced, show significant reduction in the sperm count with accumulation of p53 and cleaved caspase-3 in testicular nuclei. Taken together, the present study has demonstrated a new G(o)-coupled receptor for MIS in mediating ERK1/2 activation leading to antiapoptotic activity or cell survival.