Reference - Detail
|Author||Tran TA, Kinch L, Peña-Llopis S, Kockel L, Grishin N, Jiang H, Brugarolas J.|
|Title||Platelet-derived growth factor/vascular endothelial growth factor receptor inactivation by sunitinib results in Tsc1/Tsc2-dependent inhibition of TORC1.|
|Journal||Mol. Cell. Biol.|
Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors are implicated in development and tumorigenesis and dual inhibitors like sunitinib are prescribed for cancer treatment. While mammalian VEGF and PDGF receptors are present in multiple isoforms and heterodimers, Drosophila encodes one ancestral PDGF/VEGF receptor, PVR. We identified PVR in an unbiased cell-based RNA interference (RNAi) screen of all Drosophila kinases and phosphatases for novel regulators of TORC1. PVR is essential to sustain target of rapamycin complex 1 (TORC1) and extracellular signal-regulated kinase (ERK) activity in cultured insect cells and for maximal stimulation by insulin. CG32406 (henceforth, PVRAP, for PVR adaptor protein), an Src homology 2 (SH2) domain-containing protein, binds PVR and is required for TORC1 activation. TORC1 activation by PVR involves Tsc1/Tsc2 and, in a cell-type-dependent manner, Lobe (ortholog of PRAS40). PVR is required for cell survival in vitro, and both PVR and TORC1 are necessary for hemocyte expansion in vivo. Constitutive PVR activation induces tumor-like structures that exhibit high TORC1 activity. Like its mammalian orthologs, PVR is inhibited by sunitinib, and sunitinib treatment phenocopies PVR loss in hemocytes. Sunitinib inhibits TORC1 in insect cells, and sunitinib-mediated TORC1 inhibition requires an intact Tsc1/Tsc2 complex. Sunitinib similarly inhibited TORC1 in human endothelial cells in a Tsc1/Tsc2-dependent manner. Our findings provide insight into the mechanism of action of PVR and may have implications for understanding sunitinib sensitivity and resistance in tumors.
|MeSH||Amino Acid Sequence Animals Antineoplastic Agents / pharmacology Blotting, Western Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism* Cell Line Cell Proliferation / drug effects Cells, Cultured Drosophila Proteins / chemistry Drosophila Proteins / genetics Drosophila Proteins / metabolism* Endothelial Cells / cytology Endothelial Cells / drug effects Endothelial Cells / metabolism Hemocytes / cytology Hemocytes / drug effects Hemocytes / metabolism Humans Indoles / chemistry Indoles / metabolism Indoles / pharmacology* Mechanistic Target of Rapamycin Complex 1 Models, Molecular Molecular Sequence Data Multiprotein Complexes / antagonists & inhibitors Multiprotein Complexes / genetics Multiprotein Complexes / metabolism* Mutation Protein Structure, Tertiary Pyrroles / chemistry Pyrroles / metabolism Pyrroles / pharmacology* RNA Interference Receptor Protein-Tyrosine Kinases / chemistry Receptor Protein-Tyrosine Kinases / genetics Receptor Protein-Tyrosine Kinases / metabolism* Sequence Homology, Amino Acid TOR Serine-Threonine Kinases / antagonists & inhibitors TOR Serine-Threonine Kinases / genetics TOR Serine-Threonine Kinases / metabolism* Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism|
|WOS Category||BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY|