Type II cGMP-dependent protein kinase inhibits ligand‑induced activation of EGFR in gastric cancer cells.

Abstract

Our previous data demonstrated that type II cGMP‑dependent protein kinase (PKG II) inhibited epidermal growth factor (EGF)-induced MAPK/ERK/JNK‑mediated signal transduction through inhibiting the phosphorylation/activation of the epidermal growth factor receptor (EGFR). Since the EGFR also binds with several other ligands as well as EGF, the present study was designed to investigate whether PKG II inhibited transforming growth factor-α (TGF-α), betacellulin (BTC) and epiregulin (EPR) induced phosphorylation/activation of the EGFR and consequent MAPK/ERK‑mediated signaling. The human gastric cancer cell line AGS, was infected with adenoviral constructs encoding cDNA of PKG II (Ad-PKG II) to increase the expression of PKG II and was treated with 8-pCPT-cGMP to activate the kinase. Western blotting was applied to detect the phosphorylation of EGFR and MAPK/ERK. The results demonstrated that treatment with EGF (100 ng/ml, 5 min), TGF-α (100 ng/ml, 5 min), BTC (100 ng/ml, 5 min) and EPR (100 ng/ml, 5 min) increased the tyrosine (tyr) 1068 phosphorylation of the EGFR and the threonine (thr) 202/tyr 204 phosphorylation of MAPK/ERK. Infecting the cells with Ad-PKG II and stimulating the kinase with 8-pCPT-cGMP efficiently inhibited the phosphorylation of the EGFR and MAPK/ERK induced by EGF, TGF-α, BTC and EPR. The results indicated that PKG II also inhibits the activation of the EGFR caused by diverse ligands of the receptor.

• Authors: Lu Jiang, Yongchang Chen, Yueying Li, Ting Lan, Min Wu, Ying Wang, Hai Qian
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 9 Issue 4 Pg. 1405-9 (Apr 2014) ISSN: 1791-3004 [Electronic] Greece
• PMID: 24534906 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BTC protein, human
• Betacellulin
• EREG protein, human
• Epiregulin
• Intercellular Signaling Peptides and Proteins
• Ligands
• Transforming Growth Factor alpha
• Phosphotyrosine
• Epidermal Growth Factor
• EGFR protein, human
• ErbB Receptors
• Cyclic GMP-Dependent Protein Kinase Type II
• PRKG2 protein, human
• Extracellular Signal-Regulated MAP Kinases

Topics

• Betacellulin
• Cell Line, Tumor
• Cyclic GMP-Dependent Protein Kinase Type II (metabolism)
• Enzyme Activation (drug effects)
• Epidermal Growth Factor (pharmacology)
• Epiregulin
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Intercellular Signaling Peptides and Proteins (pharmacology)
• Ligands
• Phosphorylation (drug effects)
• Phosphotyrosine (metabolism)
• Stomach Neoplasms (enzymology, metabolism)
• Transforming Growth Factor alpha (pharmacology)