Dlxin-1, a MAGE family protein, induces accelerated neurite outgrowth and cell survival by enhanced and early activation of MEK and Akt signalling pathways in PC12 cells

Abstract

Dlxin-1 (also known as NRAGE or MAGED1) is a member of Type II melanoma-associated antigen (MAGE) family of proteins characterized by presence of a unique region of about 200 amino acids known as the MAGE homology domain (MHD). Dlxin-1 is associated with a large number of diverse cellular functions ranging from transcriptional regulation, cell cycle progression and differentiation to developmental apoptosis. While there are numerous studies reporting the role of NRAGE in facilitating cell death by interaction with p75NTR, we found varied effects of Dlxin-1 over-expression on PC12 cells grown in presence of NGF. These include induction of increased cell survival in presence of NGF and accelerated neuronal differentiation. We here categorically demonstrate that the effects on neuritogenesis are promoted through interactions of Dlxin-1 with the neurotrophin receptor TrkA. Further, using pharmacological inhibitors to specific pathways, we delineate the effects on enhanced neuritogenesis to the early and sustained activation of MEK pathway whereas the effects on cell survival to the early activation of Akt pathway. Next, we demonstrate a physical interaction of necdin with Dlxin-1 in PC12 cells. Our results establish that Dlxin-1 is an enhancer of neuronal differentiation and suggests that its possible interaction with NGF and necdin is critical in mediating pathways involved in neuronal survival and differentiation. Further in-depth analyses of the activation of various signalling pathways mediated through interaction with Dlxin-1 may provide valuable insight on the mechanisms that govern decisions regarding neuronal survival, growth, differentiation or apoptosis.