H. Honda et al., Heart-specific activation of LTK results in cardiac hypertrophy, cardiomyocyte degeneration and gene reprogramming in transgenic mice, ONCOGENE, 18(26), 1999, pp. 3821-3830
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 cyto
megarovirus enhancer and beta-actin promoter. The transgenic mice exhibited
growth retardation and most of the transgenic mice died within several mon
ths after birth, Interestingly, although LTK was expressed in several major
organs, the activation (tyrosine-phosphorylation, kinase activity, and mul
timerization) of LTK was observed selectively in the heart, where LTK was l
ocalized on intracellular membrane, presumably on endoplasmic reticulum. Ec
hocardiography 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 consi
dered to be due to apoptosis, based on the finding that the sarcolemmas of
the degenerative cardiomyocytes were well preserved. In addition, expressio
n of fetal genes, such as atrial natriuretic peptide and skeletal alpha-act
in, was markedly induced in the transgenic heart. These results indicate th
at a certain tissue-specific mechanism of activating LTK exists in the hear
t and that the activated LTK resulted in cardiac hypertrophy, cardiomyocyte
degeneration and gene reprogramming. These findings will provide novel ins
ights into the activating mechanism and biological role of LTK in vivo.