Transforming growth factor-beta1-induced degradation of activated Src tyrosine kinase in rat fibroblasts.
Transforming growth factors-beta (TGF-betas) play pivotal roles in the regulation of cell growth and differentiation, although little is known regarding the regulation of cytoplasmic components by TGF-betas. Src tyrosine kinase is required for signal transduction of various cytokine receptors, including epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and G-protein coupled receptors. Moreover, Src tyrosine kinase is important in signal cross-talk between these receptors. To determine whether Src kinase is also involved in TGF-beta signaling, we examined the effects of TGF-beta1 on Src in the rat fibroblast cell line 3Y1 and in v-Src-transformed 3Y0 (SR-3Y1). TGF-beta1 inhibited mitogen-activated protein kinase activity and inhibited growth in SR-3Y1 cells, while it did not affect the growth of 3Y1 cells. TGF-beta1 significantly decreased v-Src kinase activity and protein abundance in SR-3Y1 cells, mainly by accelerating the degradation of v-Src. In contrast, in 3Y1 cells, TGF-beta1 did not affect c-Src abundance or kinase activity. However, upon activation of c-Src in 3Y1 cells by PDGF, TGF-beta1 decreased Src abundance. Additionally, in 3Y1 cells transfected with an activated c-Src mutant which lacks the SH3 domain, its level was decreased by TGF-beta1 treatment. These findings suggest that TGF-beta1 specifically induces degradation of activated Src kinase. This may be a novel mechanism for cross-talk between growth factors and TGF-beta1.
Second Department of Internal Medicine, Osaka University Medical School, Yamadaoka, Suita, Japan.
K
K
Fukuda
S
S
Kawata
S
S
Tamura
Y
Y
Matsuda
Y
Y
Inui
T
T
Igura
S
S
Inoue
T
T
Kudara
Y
Y
Matsuzawa
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D010982:Platelet-Derived Growth Factor; D011480:Protease Inhibitors; D016212:Transforming Growth Factor beta; D016392:Proto-Oncogene Proteins pp60(c-src)