The Par-4-GRP78 TRAIL, more twists and turns

GRP78, also referred to as BiP, is an essential molecular chaperone and a master regulator of the unfolded protein response. Traditionally, GRP78 is regarded as localized in the lumen of the endoplasmic reticulum (ER). However, recent findings revealed that a subfraction of GRP78 can localize to the surface of specific cell types. Furthermore, preferential expression of GRP78 on the surface of tumor cells but not in normal organs suggests that surface GRP78 can serve both as a target as well as mediator for cancer-specific therapy. Recent reports further established that GRP78 forms complexes with specific proteins on the cell surface and plays an important role in signaling, impacting cell survival and proliferation. Burikhanov et al. (Cell 2009, 138:377) reported that Par-4, generally regarded as a cytosolic and nuclear protein that promotes cell death via the mitochondrial cell death pathway, is spontaneously secreted by normal and cancer cells and this process is enhanced by ER stress or with addition of TRAIL. It is proposed that ER stress, induced by extracellular insults such as TRAIL, causes translocation of the Par-4-GRP78 complex from the ER to the plasma membrane, and through a positive feedback loop, extracellular Par-4 binds to cell surface GRP78 and activates the extrinsic apoptotic pathway. In this journal club, we discuss some open questions and how these new findings integrate with current understanding of GRP78 function in vivo.