Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.8 (polynucleotide phosphorylase)
 723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear existence of epidermal growth factor receptor (EGFR) has been documented for more than two decades. Resistance of cancer to radiotherapy is frequently correlated with elevated EGFR expression, activity, and nuclear translocation. However, the role of nuclear EGFR (nEGFR) in radioresistance of cancers remains elusive. In the current study, we identified a novel nEGFR-associated protein, polynucleotide phosphorylase (PNPase), which possesses 3' to 5' exoribonuclease activity toward c-MYC mRNA. Knockdown of PNPase increased radioresistance. Inactivation or knock-down of EGFR enhanced PNPase-mediated c-MYC mRNA degradation in breast cancer cells, and also increased its radiosensitivity. Interestingly, the association of nEGFR with PNPase and DNA-dependent protein kinase (DNAPK) increased significantly in breast cancer cells after exposure to ionizing radiation (IR). We also demonstrated that DNAPK phosphorylates PNPase at Ser-776, which is critical for its ribonuclease activity. The phospho-mimetic S776D mutant of PNPase impaired its ribonuclease activity whereas the nonphosphorylatable S776A mutant effectively degraded c-MYC mRNA. Here, we uncovered a novel role of nEGFR in radioresistance, and that is, upon ionizing radiation, nEGFR inactivates the ribonuclease activity of PNPase toward c-MYC mRNA through DNAPK-mediated Ser-776 phosphorylation, leading to increase of c-MYC mRNA, which contributes to radioresistance of cancer cells.
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PMID:Nuclear EGFR suppresses ribonuclease activity of polynucleotide phosphorylase through DNAPK-mediated phosphorylation at serine 776. 2281 74

The epidermal growth factor receptor (EGFR) is a well-studied receptor-tyrosine kinase that serves vital roles in regulation of organ development and cancer progression. EGFR not only exists on the plasma membrane, but also widely expressed in the nucleus, endosomes, and mitochondria. Most recently, several lines of evidences indicated that autophagy is regulated by EGFR in kinase-active and -independent manners. In this review, we summarized recent advances in our understanding of the functions of different subcellularly located EGFR on autophagy. Specifically, plasma membrane- and cytoplasm-located EGFR (pcEGFR) acts as a tyrosine kinase to regulate autophagy via the PI3K/AKT1/mTOR, RAS/MAPK1/3, and STAT3 signaling pathways. The kinase-independent function of pcEGFR inhibits autophagy by maintaining SLC5A1-regulated intracellular glucose level. Endosome-located EGFR phosphorylates and inhibits Beclin1 to suppress autophagy, while kinase-independent endosome-located EGFR releases Beclin1 from the Rubicon-Beclin1 complex to increase autophagy. Additionally, the nuclear EGFR activates PRKDC/PNPase/MYC signaling to inhibit autophagy. Although the role of mitochondria-located EGFR in autophagy is largely unexplored, the production of ATP and reactive oxygen species mediated by mitochondrial dynamics is most likely to influence autophagy.
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PMID:The roles of subcellularly located EGFR in autophagy. 2842 83