PKG II reverses HGF-triggered cellular activities by phosphorylating serine 985 of c-Met in gastric cancer cells
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Yan Wu1,*, Xiaoyuan Yao2,*, Miaolin Zhu1, Hai Qian1, Lu Jiang1, Ting Lan1, Min Wu1, Ji Pang1, Yongchang Chen1
1Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province, PR China
2Basic Medical Department, Changchun Medical College, Changchun City, Jilin Province, PR China
*These authors contributed equally to this work
Yongchang Chen, email: firstname.lastname@example.org
Keywords: type II cGMP-dependent protein kinase G, phosphorylation, c-Met, inhibition, gastric cancer cell
Received: December 30, 2015 Accepted: April 10, 2016 Published: April 28, 2016
Previous studies showed that type II cGMP-dependent protein kinase G (PKG II) could inhibit the activation of epidermal growth factor receptor (EGFR). Both c-Met and EGFR belong to family of receptor tyrosine kinases (RTKs) and have high molecular analogy. However, the effect of PKG II on c-Met activation is unclear. This study was designed to investigate the inhibitory effect of PKG II on the activation of c-Met and consequent biological activities. The results from CCK8 assay, Transwell assay and TUNEL assay showed that HGF enhanced cell proliferation and migration, and decreased cell apoptosis. Activated PKG II reversed the above changes caused by HGF. Immunoprecipitation and Western blotting results showed that PKG II could bind with c-Met and phosphorylate its Ser985, and thereby inhibited HGF-induced activation of c-Met and MAPK/ERK and PI3K/Akt/mTOR mediated signal transduction. When Ser985 of c-Met was mutated to Alanine for preventing phosphorylation of this site, the blocking effect of PKG II on c-Met activation was annulled. When Ser985 of c-Met was mutated to Aspartic acid for mimicking phosphorylation of this site, HGF-induced activation of c-Met was prevented. In conclusion, the results indicated that PKG II could block c-Met activation via phosphorylating Ser985 of this RTK.
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