title: Heart-specific activation of LTK results in cardiac hypertrophy, cardiomyocyte degeneration and gene reprogramming in transgenic mice.
abstract: Leukocyte tyrosine kinase (LTK) is a receptor-type protein tyrosine kinase belonging to the insulin receptor superfamily. To elucidate its biological role, we generated transgenic mice expressing LTK under the control of cytomegarovirus enhancer and beta-actin promoter. The transgenic mice exhibited growth retardation and most of the transgenic mice died within several months after birth. Interestingly, although LTK was expressed in several major organs, the activation (tyrosine-phosphorylation, kinase activity, and multimerization) of LTK was observed selectively in the heart, where LTK was localized on intracellular membrane, presumably on endoplasmic reticulum. Echocardiography showed that the transgenic heart underwent severe concentric hypertrophy, which resulted in reduced cardiac output, low blood pressure, and increased heart rate. Histological examination of the heart exhibited focal degeneration of cardiomyocytes. These histological changes were considered to be due to apoptosis, based on the finding that the sarcolemmas of the degenerative cardiomyocytes were well preserved. In addition, expression of fetal genes, such as atrial natriuretic peptide and skeletal alpha-actin, was markedly induced in the transgenic heart. These results indicate that a certain tissue-specific mechanism of activating LTK exists in the heart and that the activated LTK resulted in cardiac hypertrophy, cardiomyocyte degeneration and gene reprogramming. These findings will provide novel insights into the activating mechanism and biological role of LTK in vivo.
authors.affiliation: Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Honda
authors.forename: K
authors.initials: K
authors.lastname: Harada
authors.forename: I
authors.initials: I
authors.lastname: Komuro
authors.forename: F
authors.initials: F
authors.lastname: Terasaki
authors.forename: H
authors.initials: H
authors.lastname: Ueno
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Kawamura
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: H
authors.initials: H
authors.lastname: Hirai
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics*; D003587:Cytomegalovirus / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000201:enzymology; D004789:Enzyme Activation; D005326:Fetal Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D006130:Growth Disorders / Q000235:genetics; D006413:Hematopoietic System / Q000166:cytology / Q000201:enzymology; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D005326:Fetal Proteins; D009124:Muscle Proteins; C489300:LTK protein, human; C064626:Ltk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases