TAILIEUCHUNG - Báo cáo khoa học: Pleiotropy of leptin receptor signalling is defined by distinct roles of the intracellular tyrosines

The leptin receptor (LEPR) is a class I cytokine receptor signalling via both the janus kinase⁄signal transducer and activator of transcription (JAK⁄STAT) and the MAP kinase pathways. In addition, leptin has been shown previously to activate AMP-activated kinase (AMPK) in skeletal muscle. To enable a detailed analysis of leptin signalling in pancreatic beta cells, LEPR point mutants with single or combined exchanges of the three intracellular tyrosines were expressed in HIT-T15 insulinoma cells | ềFEBS Journal Pleiotropy of leptin receptor signalling is defined by distinct roles of the intracellular tyrosines Paul Hekerman1 Julia Zeidler1 Simone Bamberg-Lemper1 Holger Knobelspies1 Delphine Lavens2 Jan Tavernier2 Hans-Georg Joost3 and Walter Becker1 1 Institute of Pharmacology and Toxicology MedicalFaculty of the Aachen University Germany 2 The Flanders Interuniversity Institute for Biotechnology Department of MedicalProtein Research VIB9 Ghent University Belgium 3 German Institute of Human Nutrition DIfE Potsdam-Rehbrucke Nuthetal Germany Keywords leptin leptin receptor STAT luciferase insulinoma Correspondence W. Becker Institut fuer Pharmakologie und Toxikologie Medizinische Fakultat der RWTH Aachen Wendlingweg 2 52074 Aachen Germany Fax 49 241 8082433 Tel 49 241 8089136 E-mail Received 14 July 2004 revised 9 September 2004 accepted 13 September 2004 doi The leptin receptor LEPR is a class I cytokine receptor signalling via both the janus kinase signal transducer and activator of transcription JAK STAT and the MAP kinase pathways. In addition leptin has been shown previously to activate AMP-activated kinase AMPK in skeletal muscle. To enable a detailed analysis of leptin signalling in pancreatic beta cells LEPR point mutants with single or combined exchanges of the three intracellular tyrosines were expressed in HIT-T15 insulinoma cells. Western blots with activation state-specific antibodies recognizing specific signalling molecules revealed that the wild-type receptor activated STAT1 STAT3 STAT5 and ERK1 2 but failed to alter the phosphorylation of AMPK. Each of the three intracellular tyrosine residues in LEPR exhibited different signalling capacities Tyr985 was necessary and sufficient for leptin-induced activation of ERK1 2 Tyr1077 induced tyrosyl phosphorylation of STAT5 and Tyr1138 was capable of activating STAT1 STAT3 and STAT5. Consistent results were obtained in reporter gene .

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