Phosphohexose isomerase/autocrine motility factor/neuroleukin/maturation factor is a multifunctional phosphoprotein

Metastasis Research Program, Karmanos Cancer Institute, 110 East Warren, Detroit, MI 48201, USA
Biochimica et Biophysica Acta (Impact Factor: 4.66). 08/2000; 1480(1):235-244. DOI: 10.1016/S0167-4838(00)00075-3


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.

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    • "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). "
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    Frontiers in Physiology 06/2015; 6:171. DOI:10.3389/fphys.2015.00171 · 3.53 Impact Factor
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    • "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. "
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    Cell Metabolism 05/2014; 20(1). DOI:10.1016/j.cmet.2014.04.017 · 17.57 Impact Factor
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    • "Autocrine motility factor (AMF)/Neuroleukin (NLK)/maturation factor (MF) is an extracellular phospho hexose isomerase (PHI) that is secreted from malignant or neoplastic cells [1] [2] [3]. 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 [4]. "
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    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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