Disease relevance of GP2

• Since its homologue, uromodulin, is involved in renal cast formation, we asked the question whether GP2 might play a similar role in plug formation in chronic pancreatitis [1].
• When GP2 knock-out mice were subjected to two different models of pancreatitis, no major differences were detected [2].
• GP2-deficient mice displayed no gross signs of nutrient malab-sorption such as weight loss, growth retardation, or diarrhea [2].
• The first ORF encodes a foreign polypeptide (GP2 or HGP2) containing amino acid sequences derived from the gp41 protein of human immunodeficiency virus type 1 [3].
• The ribonucleoprotein transfection system for influenza virus allowed us to construct two influenza A viruses, GP2/BIP-NA and HGP2/BIP-NA, which contained bicistronic neuraminidase (NA) genes [3].

High impact information on GP2

• Two glycoproteins, GP-1 and GP-2, have been isolated from an extracellular membrane synthesized in cell culture by an embryonal carcinoma-derived cell line [4].
• The presence of LETS protein and GP-2 in basement membranes suggests that there are subtle interactions which are important in adhesion of epithelial cells to basement membranes [4].
• This protein was confirmed as GP2 by its localization to zymogen granule membranes, its isoelectric point, and by Western blotting [1].
• GP2, the homologue to the renal cast protein uromodulin, is a major component of intraductal plugs in chronic pancreatitis [1].
• GP2, a protein in the exocrine pancreas, is a glycosyl phosphatidylinositol-anchored protein that is cleaved from the zymogen granule membrane and secreted into pancreatic juice [1].

Chemical compound and disease context of GP2

• Drug resistant variants were isolated, suggesting that these compounds act through inhibition of a viral protein, the viral glycoprotein (GP2), and not through cellular toxicity mechanisms [5].
• In the present study we compared the sensitivity to adriamycin (ADR) and the capacity of ADR uptake in two human neuroblastoma cell lines differing in properties relevant to metastatic potential, the GP2 and MB, of low- and high-malignancy phenotype, respectively [6].

Biological context of GP2

• Assignment of pancreatic zymogen granule membrane protein GP2 (GP2) to human chromosome band 9q21.11 to q21.2 by in situ hybridization [7].
• The nucleotide sequence of the human GP-2 gene was determined from cDNA clones isolated from a lambda gt11 pancreatic library [8].
• However, the mechanism by which GP2 and tyrosine kinases act together to activate endocytosis at the APM remains unknown [9].
• The pancreatic zymogen granule membrane protein GP-2 was introduced into cells of exocrine or endocrine origin by transfection of its cDNA in order to investigate the mechanisms by which proteins are specifically incorporated into the membranes of secretory granules [10].
• Proteases have been postulated to release GP-2 from the membrane, but phospholipases also have the capacity to release the protein from the membrane by hydrolysis of its peculiar glycosylphosphatidylinositol membrane anchor [11].

Anatomical context of GP2

• Expression of both forms of GP2 in the human pancreas was confirmed [12].
• GP-2 released from zymogen granule membranes with phosphatidylinositol phospholipase C reacts with anti-cross-reactive determinant antibody (anti-CRD), confirming the GPI nature of the pancreatic homologue [13].
• GP-2 homologues are observed in a wide variety of epithelial cells, several of which contain highly regulated secretory processes [13].
• Sequence of the cDNA encoding human GP-2, the major membrane protein in the secretory granule of the exocrine pancreas [8].
• This suggests that the cleavage of GP2 from the cell membrane may activate endocytosis through a tyrosine kinase-regulated pathway [9].

Associations of GP2 with chemical compounds

• A family of homologous genes is shown to encode GP-2, the major glycosylphosphatidylinositol (GPI)-linked glycoprotein of pancreatic zymogen granule membranes, and Tamm-Horsfall protein (THP), a GPI-linked glycoprotein associated with apical vesicles in kidney thick ascending limb of Henle (TALH) cells [13].
• Dot-blot assay showed that annexin IV interacts with GP-2 in the presence of calcium and that it recognizes the terminal sialic acid residues linked through alpha2-3 linkages to the carbohydrate of GP-2 [14].
• Although 93% of the GP-2 in the resting secretions of anaesthetized rats could be pelleted, Triton X-114 phase extraction showed that 70% of this GP-2 had lost its hydrophobic properties [11].
• It is therefore concluded that most of the GP-2 secreted by the pancreas of anaesthetized rats under resting conditions is released from the membrane by a phospholipase C which hydrolyses the phosphodiester bond linking GP-2 to its diradylglycerol anchor [11].
• These studies show the presence of inositol 1,2-(cyclic)monophosphate on the secreted hydrophilic GP-2, confirming the involvement of an endogenous phospholipase C in the solubilization of GP-2 by the exocrine pancreas [11].

Other interactions of GP2

• These results suggest that GP-2 is an endogenous ligand of annexin IV in the exocrine pancreas [14].
• This suggests that in pancreatic acini, GP2 may exist in a complex with src kinases, caveolin, and an 85-kDa phosphorylated substrate to regulate endocytosis at the APM [9].
• In experiments supporting the localization data, incubation of the AR42J transformants with the secretagogue cholecystokinin (CCK8) resulted in enhanced release of a shed form of GP-2 into the medium in parallel with amylase, suggesting that the two proteins were secreted from the same compartment [10].
• Poor binding of a HER-2/neu epitope (GP2) to HLA-A2.1 is due to a lack of interactions with the center of the peptide [15].
• All TCC displayed high specific proliferation, showed DR-restriction, and produced IFN-gamma upon stimulation with recombinant GP2 [16].

Analytical, diagnostic and therapeutic context of GP2

• Molecular cloning and sequences of cDNAs encoding alpha (large) and beta (small) isoforms of human pancreatic zymogen granule membrane-associated protein GP2 [12].
• In AR42J cells, GP-2 was localized by immunofluorescence and immunoelectron microscopy to the endogenous zymogen-like granules as well as to the plasma membrane [10].
• Single- and double-label immunoelectron microscopy demonstrated that these large organelles labeled with anti-GP-2 antibodies, whereas the smaller adrenocorticotropic hormone (ACTH)-containing secretory vesicles did not [10].
• Zymogen granules in the GP2 knock-out mice appeared normal on electron microscopy and contained the normal complement of proteins excluding GP2 [2].
• The identification of the HER2/neu-derived peptide GP2 as a TAA in pancreatic cancer provides an opportunity for the design of novel immunotherapy and vaccine strategies [17].

References