PDGF-BB enhances collagen gel contraction through a PI3K-PLCγ-PKC-cofilin pathway

• Published in: Scientific reports 2017-08, Vol.7 (1), p.8924-12, Article 8924
• Main Authors: Reyhani, Vahid, Tsioumpekou, Maria, van Wieringen, Tijs, Rask, Lars, Lennartsson, Johan, Rubin, Kristofer
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13; 13/1; 631/80/128/1276; 631/80/86/2368; 82/29; 96/109; 96/95; Acetic acid; Actin; Cofilin; Collagen; Cytokines; Filaments; Growth factors; Humanities and Social Sciences; Kinases; multidisciplinary; Phorbol 12-myristate 13-acetate; Phospholipase C; Phosphorylation; Platelet-derived growth factor; Platelet-derived growth factor BB; Protein kinase C; Science; Science (multidisciplinary); Signal transduction
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-08411-1

Cell-mediated contraction of collagenous matrices is modulated by various growth factors and cytokines, such as platelet-derived growth factor-BB (PDGF-BB). Here we used a genetic cell model to delineate defined signaling pathways that enhance collagen gel contraction downstream of ligand-stimulated platelet-derived growth factor receptor-β (PDGF-Rβ). Our data show that PDGF BB-enhanced activations of phosphatidylinositol 3′-kinase (PI3K) and phospholipase Cγ (PLCγ) were necessary for PDGF-enhanced collagen gel contraction. Importantly, other defined signaling pathways down-stream of PDGF-Rβ were, however, dispensable. The decisive roles for PI3K and PLCγ were corroborated by experiments using selective inhibitors. Furthermore, we show that de-phosphorylation and thereby activation of cofilin that is important for the turnover of actin filaments, is depended on PI3K and PLCγ down-stream of PDGF-Rβ. Moreover, inhibition of protein kinase C (PKC) by GÖ6976 and bisindolylmaleimide-II abolished cofilin de-phosphorylation, as well as PDGF-enhanced contraction. In contrast, activation of the PKC protein family by 4β-phorbol 12-myristate 13-acetate (PMA) did not accelerate collagen gel contraction although it induced long-term cofilin de-phosphorylation, showing the need of a dynamic control of cofilin de-phosphorylation for PDGF-enhanced collagen gel contraction. Taken together, our data point to the involvement of a PI3K/PLCγ-PKC-cofilin pathway in both PDGF-enhanced cofilin de-phosphorylation and PDGF-enhanced collagen gel contraction.