Phosphohexose isomerase (PHI) is a member of the ectoenzyme/exoenzyme family and plays a key role in both glycolysis and gluconeogenesis pathways. Upon secretion PHI acts as a cytokine with tumor autocrine motility factor (AMF), neuroleukin (NLK) and maturation factor (MF) functions. Signaling is initiated by its binding to a cell surface 78 kDa glycoprotein (gp78). However, since PHI protein is a ‘leaderless’ secretory protein, released from cells via a non-classical route(s), we questioned whether the molecule undergoes post-translation modification while retaining proper folding and maintaining intact enzymatic and motogenic activities. To address this, we have generated, expressed and isolated a recombinant human AMF (rhAMF). The rhAMF retained the biological activities of the native AMF, i.e., catalyzes phosphohexose isomerization and stimulated cell motility. Additionally, we show here that human PHI is phosphorylated at serine 185 by casein kinase II (CK II) and we provide experimental evidence suggesting that this phosphorylation is associated with secretion, thus providing insights for elucidating the intracellular signal transmission of cell response to stimulation by AMF/NLK/MF.
"For example, the phosphoglucose isomerase (PGI) is a moonlighting protein in healthy conditions. It converts Glucose 6-phosphate to Fructose 6-phosphate and also functions as a neurotrophic factor (Haga et al., 2000). Mutation leading to the inactivation of both molecular functions provokes a hemolytic anemia with neurological defects whereas a mutation impairing only the enzymatic function causes solely hemolytic anemia (Kugler et al., 1998). "
[Show abstract][Hide abstract] ABSTRACT: Moonlighting proteins are a subset of multifunctional proteins characterized by their multiple, independent, and unrelated biological functions. We recently set up a large-scale identification of moonlighting proteins using a protein-protein interaction (PPI) network approach. We established that 3% of the current human interactome is composed of predicted moonlighting proteins. We found that disease-related genes are over-represented among those candidates. Here, by comparing moonlighting candidates to non-candidates as groups, we further show that (i) they are significantly involved in more than one disease, (ii) they contribute to complex rather than monogenic diseases, (iii) the diseases in which they are involved are phenotypically different according to their annotations, finally, (iv) they are enriched for diseases pairs showing statistically significant comorbidity patterns based on Medicare records. Altogether, our results suggest that some observed comorbidities between phenotypically different diseases could be due to a shared protein involved in unrelated biological processes.
Frontiers in Physiology 06/2015; 6:171. DOI:10.3389/fphys.2015.00171 · 3.53 Impact Factor
"Interestingly, 10/30 positives were involved in the energy production and metabolism IPA network (Figure S3), including glucose-6-phosphate isomerase (gpi-1/GPI), a key enzyme in glycolysis. Interestingly, when GPI-1 is secreted by cancer cells, it can also serve as a cytokine to activate autocrine motility factor (AMF) signaling (Haga et al., 2000). It was therefore significant that the receptor for AMF (hrdl-1/AMFR) was also identified in this screen. "
[Show abstract][Hide abstract] ABSTRACT: Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson's disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from α-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.
"Autocrine motility factor (AMF)/Neuroleukin (NLK)/maturation factor (MF) is an extracellular phospho hexose isomerase (PHI) that is secreted from malignant or neoplastic cells   . AMF act in a cytokine-like manner via the autocrine motility factor receptor (AMFR) 78 kDa glyco protein (gp78), which is a seven transmembrane glycoprotein . "
[Show abstract][Hide abstract] ABSTRACT: The autocrine motility factor (AMF) is a multifunctional protein that is involved in tumor progression including enhanced invasiveness via induction of matrix metalloproteinase-3 (MMP3). The increase in MMP3 was found in an AMF-high production tumor cell line, and c-Jun, c-Fos and mitogen-activated protein kinases (MAPKs) were also highly phosphorylated compared with the parent line. AMF stimulation induced the rapid phosphorylation of the cellular MAPK cascade and MMP3 secretion, which was blocked using a specific MAPK inhibitor. Results of this study suggest that AMF stimulation stimulates MMP3 expression via a MAPK signaling pathway.
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