Type II cGMP-dependent protein kinase inhibits EGF-induced MAPK/JNK signal transduction in breast cancer cells

Abstract

Abstract. Our previous research data showed that type II cGMPdependent protein kinase (PKGII) inhibited EGF-induced MAPK/ERK-mediated signal transduction through blocking the phosphorylation of EGFR caused by EGF. Since EGFR also mediates other MAPK-mediated signal transduction pathways, this study was designed to investigate whether PKGII inhibits EGF-induced MAPK/c-Jun N-terminal kinase (JNK) signal transduction. MCF-7 human breast cancer cells were infected with adenoviral constructs encoding the cDNA of PKGII (pAd-PKGII) to increase the expression of PKGII and treated with 8-pCPT-cGMP to activate the enzyme. Western blotting was applied to detect the phosphorylation/activation of EGFR, JNK, MKK7 and c-Jun. The Pull-down method was used to detect the activation of Ras protein. Co-IP was used to analyze the binding between Grb2 and Sos1. TUNEL staining was used to detect the apoptosis of MCF-7 cells. The results showed that EGF treatment increased the phosphorylation of EGFR, the binding between Grb2 and Sos1, the activation of Ras, and the phosphorylation/activation of MKK7, JNK and c-Jun, but decreased the apoptosis of the cells. Increase of PKGII activity through infection with pAd-PKGII and stimulation with 8-pCPT-cGMP efficiently reversed the above changes caused by EGF. The results suggest that PKGII also inhibits EGF-induced MAPK/JNK-mediated signal transduction and further confirmed that PKGII can block the activation of EGFR.

The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

“…Demonstrating the difference in down-steam targets of the PKG isoforms, PKGIβ has been shown to regulate the phosphorylation of the androgen receptor and the cofactor p44 in prostate cancer cells [98]. In comparison, PKGII has been implicated in physiological functions including intestinal secretion, bone growth, learning and memory, apoptosis, and suppression of EGF signaling in breast cancer cells [99]. In addition to its profound effects on PKG activation and intracellular epithelial cell processes, cGMP signaling has also been implicated in extracellular remodeling, an important step in tumor invasion and metastasis.…”

Type II cGMP-dependent protein kinase inhibits epidermal growth factor-induced phosphatidylinositol-3-kinase/Akt signal transduction in gastric cancer cells

“…Further study in our laboratory revealed that PKG II was able to inhibit EGF-induced proliferation and migration, and inhibit MAPK-mediated signal transduction in gastric cancer cells. Notably, the inhibition was associated with the prevention of EGF-induced phosphorylation/activation of EGFR ( 11 , 12 ). As the activation of EGFR also initiates other signal transduction pathways, including the PI3K/Akt- and JAK/STAT-mediated pathways ( 5 , 13 , 14 ), further investigation into whether PKG II has an inhibitory effect on these signal pathways is required.…”

HPK1 positive expression associated with longer overall survival in patients with estrogen receptor-positive invasive ductal carcinoma-not otherwise specified

“…Tumorigenesis involves a spectrum of cellular events and processes. Activation of the MAPK and c-Jun N-terminal kinase survival and antiapoptotic signaling pathways is a crucial step in tumor cells ( 17 ). HPK1, an important member of the MAP4K family of proteins, has previously been reported to serve an important role in tumorigenesis and disease progression through its multiple roles in immunity and inflammation ( 4 ), as well as hematopoietic cell processes ( 5 ).…”