kt-5720 and Glioblastoma

kt-5720 has been researched along with Glioblastoma* in 1 studies

Other Studies

1 other study(ies) available for kt-5720 and Glioblastoma

Article	Year
Protein kinase A-dependent phosphorylation of Dock180 at serine residue 1250 is important for glioma growth and invasion stimulated by platelet derived-growth factor receptor α. Neuro-oncology, 2015, Volume: 17, Issue:6 Dedicator of cytokinesis 1 (Dock1 or Dock180), a bipartite guanine nucleotide exchange factor for Rac1, plays critical roles in receptor tyrosine kinase-stimulated cancer growth and invasion. Dock180 activity is required in cell migration cancer tumorigenesis promoted by platelet derived growth factor receptor (PDGFR) and epidermal growth factor receptor.. To demonstrate whether PDGFRα promotes tumor malignant behavior through protein kinase A (PKA)-dependent serine phosphorylation of Dock180, we performed cell proliferation, viability, migration, immunoprecipitation, immunoblotting, colony formation, and in vivo tumorigenesis assays using established and short-term explant cultures of glioblastoma cell lines.. Stimulation of PDGFRα results in phosphorylation of Dock180 at serine residue 1250 (S1250), whereas PKA inhibitors H-89 and KT5720 oppose this phosphorylation. S1250 locates within the Rac1-binding Dock homology region 2 domain of Dock180, and its phosphorylation activates Rac1, p-Akt, and phosphorylated extracellular signal-regulated kinase 1/2, while promoting cell migration, in vitro. By expressing RNA interference (RNAi)-resistant wild-type Dock180, but not mutant Dock180 S1250L, we were able to rescue PDGFRα-associated signaling and biological activities in cultured glioblastoma multiforme (GBM) cells that had been treated with RNAi for suppression of endogenous Dock180. In addition, expression of the same RNAi-resistant Dock180 rescued an invasive phenotype of GBM cells following intracranial engraftment in immunocompromised mice.. These data describe an important mechanism by which PDGFRα promotes glioma malignant phenotypes through PKA-dependent serine phosphorylation of Dock180, and the data thereby support targeting the PDGFRα-PKA-Dock180-Rac1 axis for treating GBM with molecular profiles indicating PDGFRα signaling dependency. Topics: Animals; Brain Neoplasms; Carbazoles; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cyclic AMP-Dependent Protein Kinases; Female; Glioblastoma; HEK293 Cells; Humans; Isoquinolines; Mice; Phosphorylation; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Pyrroles; rac GTP-Binding Proteins; Receptor, Platelet-Derived Growth Factor alpha; Signal Transduction; Sulfonamides	2015

Article

Year

Protein kinase A-dependent phosphorylation of Dock180 at serine residue 1250 is important for glioma growth and invasion stimulated by platelet derived-growth factor receptor α.

Neuro-oncology, 2015, Volume: 17, Issue:6

Dedicator of cytokinesis 1 (Dock1 or Dock180), a bipartite guanine nucleotide exchange factor for Rac1, plays critical roles in receptor tyrosine kinase-stimulated cancer growth and invasion. Dock180 activity is required in cell migration cancer tumorigenesis promoted by platelet derived growth factor receptor (PDGFR) and epidermal growth factor receptor.. To demonstrate whether PDGFRα promotes tumor malignant behavior through protein kinase A (PKA)-dependent serine phosphorylation of Dock180, we performed cell proliferation, viability, migration, immunoprecipitation, immunoblotting, colony formation, and in vivo tumorigenesis assays using established and short-term explant cultures of glioblastoma cell lines.. Stimulation of PDGFRα results in phosphorylation of Dock180 at serine residue 1250 (S1250), whereas PKA inhibitors H-89 and KT5720 oppose this phosphorylation. S1250 locates within the Rac1-binding Dock homology region 2 domain of Dock180, and its phosphorylation activates Rac1, p-Akt, and phosphorylated extracellular signal-regulated kinase 1/2, while promoting cell migration, in vitro. By expressing RNA interference (RNAi)-resistant wild-type Dock180, but not mutant Dock180 S1250L, we were able to rescue PDGFRα-associated signaling and biological activities in cultured glioblastoma multiforme (GBM) cells that had been treated with RNAi for suppression of endogenous Dock180. In addition, expression of the same RNAi-resistant Dock180 rescued an invasive phenotype of GBM cells following intracranial engraftment in immunocompromised mice.. These data describe an important mechanism by which PDGFRα promotes glioma malignant phenotypes through PKA-dependent serine phosphorylation of Dock180, and the data thereby support targeting the PDGFRα-PKA-Dock180-Rac1 axis for treating GBM with molecular profiles indicating PDGFRα signaling dependency.

Topics: Animals; Brain Neoplasms; Carbazoles; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cyclic AMP-Dependent Protein Kinases; Female; Glioblastoma; HEK293 Cells; Humans; Isoquinolines; Mice; Phosphorylation; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Pyrroles; rac GTP-Binding Proteins; Receptor, Platelet-Derived Growth Factor alpha; Signal Transduction; Sulfonamides

2015