The critical role of GRP78 in physiologic and pathologic stress

Abstract

GRP78 is a major endoplasmic reticulum chaperone as well as a master regulator of the unfolded protein response. In addition to playing an essential role in early embryonic development, recent studies have emerged specifically implicating GRP78 and chaperone integrity in the aging process and age-related diseases. Another exciting discovery is the regulation of GRP78 by insulin/IGF-1 signaling pathways impacting cell proliferation and survival. Mouse models of cancer, in combination with cell culture studies, validate the critical role of GRP78 in tumorigenesis and tumor angiogenesis. Further, these studies demonstrate the ability of GRP78 to suppress oncogenic PI3K/AKT signaling. The discovery of cell surface GRP78, in cancer cells and cells undergoing ER stress, presents a novel therapeutic strategy.

Figure 1

Aging leads to ER stress. The physiological process of aging can lead to ER stress via three main mechanisms; increased oxidative damage, decline in chaperone expression and activity, and reduced adaptive capacity of the ER. Prolonged ER stress contributes in part to age related disease development.

Figure 2

Triggering of adaptive UPR by Grp78 haploinsufficiency suppresses detrimental effects of diet induced stress. Grp78+/− mice subjected to chronic ER stress induced by high fat diet activate the adaptive UPR in a tissue and genetic background dependent manner, leading to increased ER chaperones and improved metabolic phenotypes.

Figure 3

The role of GRP78 in physiologic and pathologic stress. GRP78 in the ER plays a critical role in physiologic processes such as development, aging, and insulin/IGF-1 signaling. ER GRP78 serves to properly fold proteins, regulate UPR signaling, maintain chaperone homeostasis, and protect against apoptosis. GRP78 also plays an important role in a number of pathological conditions, including cancer, diabetes, obesity, and acute pancreatitis. Under ER stress conditions, and particularly in cancer, a subfraction of GRP78 translocates to the plasma membrane and is expressed on the cell surface. Cell surface GRP78 can function as a receptor, augment growth signaling, apoptotic signaling, and presents a potential therapeutic target in cancer treatment. N nucleus; ER endoplasmic reticulum; C cytoplasm; Bik Bcl-2-interacting killer; C-7 pro-caspase-7; IRE1 inositol-requiring enzyme 1; PERK PKR-like endoplasmic reticulum kinase; ATF6 activating transcription factor 6; GRP78; nascent protein.