Platelet-derived Growth Factor-DD Targeting Arrests Pathological Angiogenesis by Modulating Glycogen Synthase Kinase-3β Phosphorylation

Abstract

Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3␤ (GSK3␤) Ser 9 phosphorylation and Tyr 216 dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3␤ activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3␤ and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.

Canonical Wnt suppressor, Axin2, promotes colon carcinoma oncogenic activity

“…2E). In tandem with increased levels of Snail1 protein, levels of p-GSK3β(S9), an inactive form of the kinase (15)(16)(17), decrease slightly, whereas protein levels of p-GSK3β(Y216), the catalytically active form of the kinase, fall to background (Fig. 2E).…”

“…3B and Fig. S5) (15)(16)(17). Axin2 silencing did not affect cytosolic levels of p-GSK3β(Y216), cytosolic GSK3β kinase activity, or β-catenin content (Fig.…”

“…Instead, nuclear Axin2 directly inhibited nuclear GSK3β activity without affecting its cellular distribution. Currently, the mechanisms by which Axin2 alters GSK3β activity and phosphorylation remain the subject of conjecture, but recent studies have linked changes in GSK3β Y216 phosphorylation and/or activity to a variety of factors, including PDGF-DD signaling or p38 MAPK activity (17,36). Independent of changes in nuclear GSK3β activity, Axin2-GSK3β binding interactions can potentially alter the ability of kinase to recognize and phosphorylate target substrates (37).…”

Platelet-Derived Growth Factor Signaling in the Lung. From Lung Development and Disease to Clinical Studies

“…PDGF-D is thought to stimulate extracellular matrix deposition and angiogenesis. Studies also indicate involvement in hepatic and renal fibrosis (130). Moreover, PDGF-C and PDGF-D expression was associated with tumor development and progression (18,(131)(132)(133).…”

Radiation-induced Cancer Cell Repopulation: A Possible Mechanism Implied by Experiments Using Transplantable Mouse-derived Sarcoma Cell Line

“…Several cell-cycle related genes were up-regulated: cyclin A2 (2.5-fold), cyclin B2 (2.2-fold), and PCNA (2.3-fold). Angiogenesis-related genes were also up-regulated: T-box 1 transcription factor (7.3-fold) (Kobayashi et al, 2002) and PDGF (2.5-fold) (Kumar et al, 2010). Interestingly, one of the cancer stem cell markers, CD34 (Pierce et al, 2008), was up-regulated (4.0-fold).…”