PKG II inhibits PDGF‐BB triggered biological activities by phosphorylating PDGFRβ in gastric cancer cells

Abstract

Previous studies revealed that type II cGMP-dependent protein kinase G (PKG II) could inhibit the activation of epidermal growth factor receptor (EGFR) which is a widely investigated RTK. PDGFR belongs to family of receptor tyrosine kinases (RTKs) too. However, the effect of PKG II on PDGFR activation is not clear yet. This study investigated potential regulatory effect of PKG II on activation of PDGFRβ and the downstream signaling transductions in gastric cancer. The results from CCK8 assay and Transwell assay indicated that PDGF-BB induced cell proliferation and migration. Activated PKG II reversed the above variations caused by PDGF-BB. Immunoprecipitation and Western blotting results showed that PKG II combined with PDGFRβ and phosphorylated this receptor, and thereby inhibited PDGF-BB induced activation of PDGFRβ, and MAPK/ERK and PI3K/Akt mediated signal transduction pathways. Based on the prediction by phosphorylation site software, Ser643 and Ser712 were mutated to alanine respectively which prevented phosphorylation at these sites. Mutation at Ser712 abolished the inhibitory function of PKG II on PDGFRβ activation but mutation of Ser643 had no such an effect, indicating that Ser712 was PKG II-specific phosphorylating site of PDGFRβ. In conclusion, PKG II inhibited PDGFRβ activation in gastric cancer via phosphorylating Ser712 of this RTK.

Secretory type II cGMP‐dependent protein kinase blocks activation of PDGFRβ via Ser254 in gastric cancer cells

“…Previous studies from our lab have found that PKG II blocked the activation of PDGFRβ by PDGF-BB, thereby inhibiting signal transduction initiated by PDGFRβ and related cell proliferation, migration, and other activities (Y. Wang et al, 2018). In addition, our recent data confirmed that PKG II could be secreted out of the cell and existed in the supernatant of cultured cells and human and mouse serum.…”

“…As a serine/threonine protein kinase localized on the inner side of the cell membrane by myristoylation of the second glycine at the N‐terminal of the peptide chain, our lab found that PKG II inhibited the activation of several RTKs by phosphorylating specific sites in the intracellular domain of RTKs (Lan et al, 2019 ; Y. Wang et al, 2018 ; Wu et al, 2016 ). Based on the discovery of the secretion of PKG II, whether secretory PKG II inhibits the activation of RTKs by phosphorylating the extracellular segment of RTKs is worthy of further discussion.…”

“…Recently, more and more evidence show that PKG II is involved in regulating biological activities such as cell proliferation, migration, apoptosis and differentiation, and is closely related to the occurrence and development of tumors (Cook & Haynes, 2004 ; Fallahian et al, 2011 ; Swartling et al, 2009 ). Previous studies from our lab have found that PKG II blocked the activation of PDGFRβ by PDGF‐BB, thereby inhibiting signal transduction initiated by PDGFRβ and related cell proliferation, migration, and other activities (Y. Wang et al, 2018 ). In addition, our recent data confirmed that PKG II could be secreted out of the cell and existed in the supernatant of cultured cells and human and mouse serum.…”

“…of the cell membrane by myristoylation of the second glycine at the N-terminal of the peptide chain, our lab found that PKG II inhibited the activation of several RTKs by phosphorylating specific sites in the intracellular domain of RTKs(Lan et al, 2019;Y. Wang et al, 2018;Wu et al, 2016).…”

Low STYK1 expression indicates poor prognosis in gastric cancer

“…RPTKs are key players in the regulation of numerous fundamental cellular processes such as growth, adhesion, differentiation, and migration 26. In GC cells, the MAPK–ERK and PI3K– AKT signaling pathways affect RPTK activity 27. Therefore, we speculated that the effect of other regulatory factors in GC leads to PI3K–AKT signaling pathway feedback acting on STYK1, thereby reducing its expression.…”