Table 1 Types of GRPs with their important functions

GRP75 (mtHSP70)

Human HSPA9 encodes GRP75, a 75-kDa protein that is otherwise known as Mortalin. GRP75 is localized primarily in the mitochondria and functions as a chaperone for mitochondrial proteins. It could also be found on the plasma membranes, and in the endoplasmic reticulum and mitochondria-associated ER membrane. The different subcellular localization of GRP75 confers on it different physiological functions which include regulation of cell cycle, response to stress, generation of metabolic energy, membrane transportation, regulation of the folding, assembly, and maintenance of mitochondrial proteins. In many malignancies, GRP75 expression is increased, and several effects, such as inactivating the tumor suppressor p53, regulating apoptosis, and enhancing cancer stemness. Its other pathophysiological functions include stimulation of the proliferation and immortality of cancer cells and facilitation of cancer resistance to chemotherapy

(Wadhwa et al. 2002, 1993; Li et al. 2022; Yoon et al. 2022)

GRP78

(BiP)

GRP78, also known as immunoglobulin heavy chain-binding protein (BiP), is a chaperone protein that is primarily located in the endoplasmic reticulum (ER) of eukaryotic cells. It plays a crucial role in protein folding and quality control, ensuring proper protein maturation and preventing the accumulation of misfolded or unfolded proteins. GRP78 is a member of the heat shock protein 70 (HSP70) family and is highly conserved across species. Protein folding in the ER is a complex process, and GRP78 acts as a master regulator by binding to unfolded or misfolded proteins, preventing their aggregation, and promoting their correct folding. It possesses an ATPase activity, which allows it to cycle between its ATP-bound state (active) and its ADP-bound state (inactive), facilitating the binding and release of client proteins. In addition to its role in protein folding, GRP78 is involved in maintaining ER homeostasis. It interacts with transmembrane sensor proteins such as PERK (protein kinase RNA-like ER kinase), ATF6 (activating transcription factor 6), and IRE1 (inositol-requiring enzyme 1), which are key components of the unfolded protein response (UPR). The UPR is an adaptive signaling pathway that is activated in response to ER stress, aiming to restore ER function and alleviate the accumulation of unfolded proteins. GRP78 plays a critical role in activating and regulating the UPR, ensuring that the cellular response to ER stress is appropriately controlled

(Shiu et al. 1977; Ni and Lee 2007; Li et al. 2008; Hendershot et al. 1995; Pfaffenbach and Lee 2011; Zhu and Lee 2015; Wang et al. 2009; Gardner et al. 2013; Walter and Ron 2011)

GRP94

GRP94, otherwise known as tumor rejection antigen 1TRA1, is predominantly located in the endoplasmic reticulum and functions as a chaperone for secretory and membrane proteins. It is a cellular protein that is rapidly synthesized during glucose depletion, oxidative stress, distorted ER actions, accumulation of misfolded proteins, and ER calcium depletion. It is divided into four major domains: The N terminal domain, the middle domain, the charged linker region and the C-terminal domain. GRP94 has three main functions, first, as a molecular chaperon essential for proper folding and quality control of client proteins. It is also a calcium regulator in the ER where it supports calcium ion storage and stabilize the intracellular concentration of calcium ion. Lastly, GRP94 appears to be a key regulator of immune system. Just like other GRPs, GRP94 upregulation is documented in different cancers. GRP94 plays significant role in cancer progression and metastasis by promoting cancer cell proliferation, tumor growth, tumor angiogenesis and cancer cell invasion and metastasis. Some reports also show that GRP94 facilitates tumor resistance to therapy

(Koch et al. 1986; Mazzarella and Green 1987; Maki et al. 1990; Johnson 2012; Ni and Lee 2007; Schild and Rammensee 2000; Kim et al. 2021; Duan and Xin 2020)

GRP170

GRP170 is the largest member of GRPs. Its synthesis is induced by glucose deprivation and other stress inducers such as hypoxia, calcium imbalance, ischemia, inhibition of proteasome and non-steroidal anti-inflammatory drugs. GRP170 is structurally related to GRP78 as they both have N-terminal nucleotide binding domain, substrate binding domain, and an alpha-helical C terminus domain. GRP170 facilitates protein folding, assembly, and transport across membranes. It also plays a role in antigen presentation and immune responses. More so, it is proven to be a highly efficient ATP-binding protein in the microsome. Its role as a nucleotide exchange factor is recently reported. During the development and progression of cancers, GRP170 plays crucial roles. For instance, it contributes to tumor invasiveness, tumor survival, angiogenesis, and tumor metastasis

(Chen et al. 1996; Kuwabara et al. 1996; Sciandra et al. 1984; Wang et al. 2014)

GRP58 (ERp57)

Glucose regulated protein 58 kDa is an endoplasmic reticulum protein that is secreted in response to stress such as glucose shortage in living system. GRP58 is structurally related to disulfide isomerase. Although it localizes majorly in the ER, it is also found in the cytosol and nucleus. Within the cytosolic portion, GRP58 functions as a chaperone during the process of transduction and activation of transcriptional signaling. It facilitates the formation of complexes between STAT3 and scaffolding proteins. Once inside the nucleus, STAT3 and these proteins are recognized as integral components of matrix proteins, which play a vital role in attaching DNA to the nuclear matrix and creating DNA loops. Under normal circumstances, GRP58 binds with calreticulin and calnexin to form complexes that co-interact with glycoproteins in the endoplasmic reticulum, thereby acting as chaperone in the anabolism of glycoproteins. However, both upregulation and downregulation of GRP58 are involved in carcinogenesis. Upregulation of GRP58 is widely reported in various cancers such as ovary, stomach, lung, uterus, and breast cancers. Interestingly, its downregulation is also identified in esophageal, renal cell, gastric and cervical cancers

(Hafiza and Latifah 2014; Celli and Jaiswal 2003; Hirano et al. 1995; Frickel et al. 2004)