title: Small molecule-mediated TGF-β type II receptor degradation promotes cardiomyogenesis in embryonic stem cells.
abstract: The cellular signals controlling the formation of cardiomyocytes, vascular smooth muscle, and endothelial cells from stem cell-derived mesoderm are poorly understood. To identify these signals, a mouse embryonic stem cell (ESC)-based differentiation assay was screened against a small molecule library resulting in a 1,4-dihydropyridine inducer of type II TGF-β receptor (TGFBR2) degradation-1 (ITD-1). ITD analogs enhanced proteasomal degradation of TGFBR2, effectively clearing the receptor from the cell surface and selectively inhibiting intracellular signaling (IC(50) ~0.4-0.8 μM). ITD-1 was used to evaluate TGF-β involvement in mesoderm formation and cardiopoietic differentiation, which occur sequentially during early development, revealing an essential role in both processes in ESC cultures. ITD-1 selectively enhanced the differentiation of uncommitted mesoderm to cardiomyocytes, but not to vascular smooth muscle and endothelial cells. ITD-1 is a highly selective TGF-β inhibitor and reveals an unexpected role for TGF-β signaling in controlling cardiomyocyte differentiation from multipotent cardiovascular precursors.
authors.affiliation: Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. ewillems@sanfordburnham.org
authors.forename: Erik
authors.initials: E
authors.lastname: Willems
authors.forename: Joaquim
authors.initials: J
authors.lastname: Cabral-Teixeira
authors.forename: Dennis
authors.initials: D
authors.lastname: Schade
authors.forename: Wenqing
authors.initials: W
authors.lastname: Cai
authors.forename: Patrick
authors.initials: P
authors.lastname: Reeves
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Bushway
authors.forename: Marion
authors.initials: M
authors.lastname: Lanier
authors.forename: Christopher
authors.initials: C
authors.lastname: Walsh
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhausen
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisua Belmonte
authors.forename: John
authors.initials: J
authors.lastname: Cashman
authors.forename: Mark
authors.initials: M
authors.lastname: Mercola
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000172:deficiency / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008970:Molecular Weight; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D004095:Dihydropyridines; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; C489450:Tdgf1 protein, mouse; D004815:Epidermal Growth Factor; C038806:1,4-dihydropyridine; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II