title: The MEK1 inhibitors UO126 and PD98059 block PDGF-AB induced phosphorylation of threonine 292 in porcine smooth muscle cells.
abstract: PDGF-AB and FGF-2 (GFs) induce smooth muscle cell (SMC) proliferation which is indispensible for arteriogenesis. While there is common agreement that GFs stimulate SMC proliferation through phosphorylation (P-) of MEK1/2 at Ser218/222, we previously demonstrated that the MEK inhibitors PD98059 and UO126 did not inhibit P-Ser218/222 as originally proposed but caused strong hyperphosphorylation. Here, we demonstrate that GFs increased phosphorylation of MEK1 at Thr292 while UO126 and PD98059 blocked this phosphorylation. This was again surprising since phosphorylation of Thr292 is regarded as a negative feedback loop. Our findings suggest that inhibition of Thr292 phosphorylation in combination with hyperphosphorylation of Ser218/222 serves as an "off" switch of SMC proliferation and potentially of arteriogenesis.
authors.affiliation: Department of Cardiac Surgery, Kerckhoff-Clinic, Benekestrasse 2-8, Bad Nauheim 61231, Germany; Res Group Vascular Genomics, Kerckhoff Clinic, Benekestrasse 2-8, Bad Nauheim 61231, Germany. Electronic address: thomas.kubin@mpi-bn.mpg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kubin
authors.affiliation: Department of Cardiac Surgery, Kerckhoff-Clinic, Benekestrasse 2-8, Bad Nauheim 61231, Germany.
authors.forename: Ayse
authors.initials: A
authors.lastname: Cetinkaya
authors.affiliation: Department of Cardiac Surgery, Kerckhoff-Clinic, Benekestrasse 2-8, Bad Nauheim 61231, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schönburg
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Johann-Wolfgang-Goethe University Hospital, Theodor-Stem-Kai 7, 60590 Frankfurt/Main, Germany.
authors.forename: Andres
authors.initials: A
authors.lastname: Beiras-Fernandez
authors.affiliation: Department of Cardiac Surgery, Kerckhoff-Clinic, Benekestrasse 2-8, Bad Nauheim 61231, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.affiliation: Department of Cardiac Surgery, Kerckhoff-Clinic, Benekestrasse 2-8, Bad Nauheim 61231, Germany. Electronic address: m.richter@kerckhoff-klinik.de.
authors.forename: Manfred
authors.initials: M
authors.lastname: Richter
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology*; D002478:Cells, Cultured; D005419:Flavonoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034421:Sus scrofa; D013912:Threonine / Q000378:metabolism
chemical_list: D002070:Butadienes; D005419:Flavonoids; D009570:Nitriles; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; C113580:U 0126; C095477:platelet-derived growth factor AB; D013912:Threonine; D048369:MAP Kinase Kinase 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Arteriogenesis; Cytokines; Growth factors; MEK1/2; Signal transduction