Type II cGMP-dependent protein kinase negatively regulates fibroblast growth factor signaling by phosphorylating Raf-1 at serine 43 in rat chondrosarcoma cells

Kamemura, Norio; Murakami, Sara; Komatsu, Hiroaki; Sawanoi, Masahiro; Miyamoto, K.; Ishidoh, Kazumi; Kishimoto, Kenji; Tsuji, Akihiko; Yuasa, Keizo

doi:10.1016/j.bbrc.2017.01.001

Cited by 18 publications

(10 citation statements)

References 30 publications

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“…An important pathway by which NPR2 guanylyl cyclase activity increases bone elongation is by elevating cGMP and activating the cGMP-dependent protein kinase PRKG2 ( Pfeifer et al, 1996 ; Chikuda et al, 2004 ). Previous studies have established that application of CNP to increase NPR2 guanylyl cyclase activity in chondrocytes, thus elevating cGMP and stimulating cGMP-dependent protein kinase, inhibits FGF-induced MAP kinase activation ( Yasoda et al, 2004 ; Krejci et al, 2005 ; Ozasa et al, 2005 ; Kamemura et al, 2017 ), which would counteract FGF-inhibition of bone growth (solid blue line in Figure 7 ). Other mechanisms (for example, see Kawasaki et al, 2008 ) may also contribute to how PRKG2 activity increases bone growth (dotted blue line in Figure 7 ).…”

Section: Discussionmentioning

confidence: 93%

Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor

Shuhaibar

Robinson

Vigone

et al. 2017

eLife

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Activating mutations in fibroblast growth factor (FGF) receptor 3 and inactivating mutations in the NPR2 guanylyl cyclase both cause severe short stature, but how these two signaling systems interact to regulate bone growth is poorly understood. Here, we show that bone elongation is increased when NPR2 cannot be dephosphorylated and thus produces more cyclic GMP. By developing an in vivo imaging system to measure cyclic GMP production in intact tibia, we show that FGF-induced dephosphorylation of NPR2 decreases its guanylyl cyclase activity in growth plate chondrocytes in living bone. The dephosphorylation requires a PPP-family phosphatase. Thus FGF signaling lowers cyclic GMP production in the growth plate, which counteracts bone elongation. These results define a new component of the signaling network by which activating mutations in the FGF receptor inhibit bone growth.

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Section: Discussionmentioning

confidence: 93%

Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor

Shuhaibar

Robinson

Vigone

et al. 2017

eLife

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“…For example, PKG II has been reported to inhibit fibroblast growth factor (FGF)-induced MAPK activation via phosphorylation of Raf-1 at Ser43 in rat chondrosarcoma cells. 40 GSK-3β has also been identified as a target protein of PKG II. PKG II could directly phosphorylate GSK-3 at Ser9 in chondrocytes, inactivating GSK-3 kinase activity and enhancing hypertrophic differentiation.…”

Section: Discussionmentioning

confidence: 99%

The constitutively active PKG II mutant effectively inhibits gastric cancer development via a blockade of EGF/EGFR-associated signalling cascades

Yuan

et al. 2018

Ther Adv Med Oncol

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Type II cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG II) is a membrane-anchored enzyme expressed mainly in the intestinal mucosa and the brain, and is associated with various physiological or pathological processes. Upregulation of PKG II is known to induce apoptosis and inhibit proliferation and metastasis of cancer cells. The inhibitory effect of PKG II has been shown to be dependent on the inhibition of the activation of epidermal growth factor receptor (EGFR) and blockade of EGFR downstream signal transduction in vitro. However, it remains unclear whether similar phenomena/mechanisms exist in vivo and whether these effects are independent of cGMP or cGMP analogues. In the present work, nude mice with transplanted orthotopic tumours were infected with adenovirus encoding cDNA of constitutively active PKG II mutant (Ad-a-PKG II) and the effect of constitutively active PKG II (a-PKG II) on tumour development was detected. The results showed that a-PKG II effectively ameliorated gastric tumour development through delaying the growth, inducing the apoptosis, and inhibiting the metastasis and angiogenesis. The effect was related to blockade of EGFR activation and abrogation of the downstream signalling cascades. These findings provide novel insight which will benefit the development of new cancer therapies.

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“…Lumican-deficient cells did not exhibit the further downregulation of cell growth when treated with the ERK1/2 inhibitor, indicating that ERK1/2 participation was necessary for the lumican effect. Previously it has been suggested that ERK1/2 exerts pro-oncogenic effects in chon-drosarcoma cells ( 56 , 57 ).…”

Section: Discussionmentioning

confidence: 99%

Lumican mediates HTB94 chondrosarcoma cell growth via an IGF‑IR/Erk1/2 axis

et al. 2020

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Chondrosarcoma is a malignant bone tumor characterized by the production of a modified cartilage-type extracellular matrix (ECM). In the present study, the expression levels of the small leucine-rich proteoglycans (SLRPs), decorin, biglycan and lumican, were examined in the HTB94 human chondrosarcoma cell line. HTB94 cells were found to express and secrete the 3 SLRP members. RT-qPCR and western blot analysis demonstrated that lumican was the most abundantly secreted SLRP, whereas decorin and biglycan expression levels were low. The utilization of short interfering RNA specific for the decorin, biglycan, and lumican genes resulted in the efficient downregulation of the respective mRNA levels (P≤0.001). The growth of the HTB94 cells was stimulated by lumican (P≤0.001), whereas their migration and adhesion were not affected (P=NS). By contrast, these cellular functions were not sensitive to a decrease in low endogenous levels of decorin and biglycan. Lumicandeficiency significantly inhibited both basal and insulin-like growth factor I (IGF-I)-induced HTB94 cell growth (P≤0.001 andP≤0.01, respectively). These effects were executed through the insulin-like growth factor I receptor (IGF-IR), whose activation was markedly attenuated (P≤0.01) in lumican-deficient HTB94 cells. The downregulation of lumican induced the substantial inhibition of extracellular regulated kinase (ERK1/2) activation (P≤ 0.01), indicating that ERK1/2 is a necessary component of lumican/IGF-IR-mediated HTB94 cell proliferation. Moreover, the lumican-deficient cells exhibit increased mRNA levels of p53 (P≤0.05), suggesting that lumican facilitates HTB94 cell growth through an IGF-IR/ERK1/2/p53 signaling cascade. On the whole, the findings of the present study demonstrate that endogenous lumican is a novel regulator of HTB94 cell growth.

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Type II cGMP-dependent protein kinase negatively regulates fibroblast growth factor signaling by phosphorylating Raf-1 at serine 43 in rat chondrosarcoma cells

Cited by 18 publications

References 30 publications

Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor

Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor

The constitutively active PKG II mutant effectively inhibits gastric cancer development via a blockade of EGF/EGFR-associated signalling cascades

Lumican mediates HTB94 chondrosarcoma cell growth via an IGF‑IR/Erk1/2 axis

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