The expression of Grp78/BiP varies with tissue type, developmental stage and stress conditions. While the expression of Grp78/BiP in adult tissues is usually low under non-stress conditions, cancer cells show up-regulated levels of Grp78/BiP. Moreover, the expression of Grp78/BiP is induced upon exposure to ageing-related, environmental or genetic stressors culminating in the aggregation of misfolded proteins and the dysfunction of protein homeostasis in the ER 4. Data raised by the group of Robert Clarke provided evidence for a novel homeostatic function of Grp78/BiP in mediating lipid metabolism as targeting Grp78/BiP was found to specifically inhibit de novo fatty acid synthesis in tumor cells and to diminish mitochondrial β-oxidation through CPT1A (carnitine palmitoyltransferase 1A ) inhibition 5.
In numerous tumor cells, Grp78/BiP is located to the cell membrane where it affects oncogenic pathways promoting tumor growth and invasivenness 134, 135. Membrane-associated Grp78/BiP has been shown to serve as a multifunctional receptor interacting with the plasma proteinase inhibitor α2-macroglobulin (α2M) 136. Cell surface-associated Grp78/BiP has also been found as being involved in cell-matrix adhesion by regulating focal adhesion kinase (FAK) and interacting with α1-integrin 137. Several investigations imply a pivotal role of the α2M-Grp78/BiP system in regulating the oncogenic PI3K/AKT pathway thereby modulating growth, metastasis and chemoresistance of tumor cells 123, 136, 138, 139. The α2M-Grp78/BiP system was also defined to control cell transformation and the induction of numerous c-Myc target genes 136 as well as the activation of the aerobic glycolysis and de novo fatty acid synthesis 140. According to Gopal and colleagues, membrane-bound Grp78/BiP promotes tumor cell histone acetylation thus modulating the Warburg effect in cancer cells by stimulating pro-survival signaling pathways 141. There is a wealth of evidence illustrating an active secretion of Grp78/BiP by tumor cells which in turn stimulates differentiation and growth of tumor cells through autocrine or paracrine mechanisms, respectively 142, 143. As mentioned earlier, Grp78/BiP was identified as an extracellular molecule in the human periphery 125. Secreted Grp78/BiP has also been detected in the oviduct where it is crucially involved in sperm-zona pellucida binding 144. Recent evidence suggests a potent anti-inflammatory and immunomodulatory quality of extracellular Grp78/BiP by expressing an anti-inflammatory cytokine profile 12, 130.
A growing body of evidence indicates the contribution of Grp78/BiP to the process of cytoskeletal remodeling. Investigations by Birukova et al. clearly demonstrated that cell membrane anchorage of Grp78/BiP occurs through binding to the DnaJ-like ER co-chaperone HTJ-1/MTJ-1 11. Membrane integration of Grp78/HTJ-1 is facilitated by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC), a phospholipid which directly interacts with Grp78/BiP and targets the Grp78/HTJ-1 complex to caveolin-enriched microdomains 11. The membrane-associated complex then activates the Src/Fyn kinase followed by the assembly of the PI3K complex and subsequent activation of mTOR, sphingosine-1-phosphate receptor 1 and Rac1 GTPase, collectively leading to cytoskeletal re-organization in endothelial cells 11.