Transforming growth factor-β1-induced degradation of activated Src tyrosine kinase in rat fibroblasts

Fukuda, Kazuto; Kawata, Satoshi; Tamura, Shinji; Matsuda, Yukihiko; Inui, Yoshiaki; Igura, Takumi; Inoue, Satoshi; Kudara, Takahiko; Matsuzawa, Yūji

doi:10.1038/sj.onc.1201896

Cited by 16 publications

(16 citation statements)

References 28 publications

(32 reference statements)

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“…Increased levels of Smad3 or Smad4 can induce apoptosis (45). In the present study, however, TGF-␤1 neither induced apoptosis (data not shown) nor cell growth inhibition in HRA cells.…”

Section: Discussioncontrasting

confidence: 41%

Transforming Growth Factor-β1-dependent Urokinase Up-regulation and Promotion of Invasion Are Involved in Src-MAPK-dependent Signaling in Human Ovarian Cancer Cells

Tanaka

Kobayashi

Suzuki

et al. 2004

Journal of Biological Chemistry

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Urokinase-type plasminogen activator (uPA) has been implicated in tumor cell invasion and metastasis. We reported previously that transforming growth factor (TGF)-␤1 induces a dose-and time-dependent up-regulation of uPA mRNA and protein in highly invasive human ovarian cancer cell line HRA, leading to invasion. To further elucidate the mechanism of the invasive effect of TGF-␤1, we investigated which signaling pathway transduced by TGF-␤1 is responsible for this effect. Here, we show that 1) nontoxic concentrations of TGF-␤1 activated Src kinase; 2) TGF-␤1 rapidly phosphorylates ERK1/2 and Akt, but not p38; 3) pharmacological Src inhibitor PP2 or antisense (AS) c-Src oligodeoxynucleotide (ODN) treatment reduced TGF-␤1-induced phosphorylation of ERK1/2 and Akt by 85-90% compared with controls; 4) pharmacological inhibition of MAPK by PD98059 abrogated TGF-␤1-mediated Akt stimulation, whereas TGF-␤1-induced ERK1/2 stimulation was not inhibited by PI3K inhibitor LY294002 or AS-PI3K ODN transfection; 5) up-regulation of uPA mRNA in response to TGF-␤1 was almost totally blocked by PP2 and PD98059 and partially (ϳ55%) by LY294002; 6) TGF-␤1-induced uPA mRNA up-regulation was inhibited by treatment with AS ODNs to c-Src or PI3K by 90 or 60%, respectively, compared with control ODN treatment; and 7) blockade of the release of the transcription factor NF-B by pyrrolidinedithiocarbamate reduced the TGF-␤1-induced activation of the uPA gene by ϳ65%. In addition, curcumin, a blocker of the transcriptional factor AP-1, partially (35%) canceled this effect. Taken together, these data support a role for TGF-␤1 activation of two distinct pathways (Src-MAPK-PI3K-NF-B-dependent and Src-MAPK-AP-1-dependent) for TGF-␤1-dependent uPA up-regulation and promotion of invasion.The processes of ovarian cancer dissemination are characterized by altered local proteolysis, cellular proliferation, cell attachment, and invasion, suggesting that the urokinase-type plasminogen activator (uPA) 1 could be involved in the pathogenesis of peritoneal dissemination (1). uPA is a serine protease associated with various pathological conditions including tumor invasion and metastasis (2). One of the factors regulating the metastatic process is considered to be transforming growth factor-␤ (TGF-␤), which is a multifunctional cytokine that elicits numerous cellular effects pertinent to the metastatic process (1). TGF-␤ regulates a wide range of physiological and pathological cellular processes, including cell growth, differentiation, invasion, migration, mesenchymal transition, extracellular matrix synthesis, and cell death in many cell types including ovarian cancer cells (3). Recent data demonstrated that TGF-␤ specifically stimulates up-regulation of uPA mRNA and protein in certain types of neoplastic cells (1). The cellular mechanism(s) of the TGF-␤-induced uPA-dependent tumor invasion and metastasis has been extensively studied. The identity of the signaling pathway(s) involved in the TGF-␤-induced uPA up-regulation (4) remains less known. In a well...

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“…Increased levels of Smad3 or Smad4 can induce apoptosis (45). In the present study, however, TGF-␤1 neither induced apoptosis (data not shown) nor cell growth inhibition in HRA cells.…”

Section: Discussioncontrasting

confidence: 41%

Transforming Growth Factor-β1-dependent Urokinase Up-regulation and Promotion of Invasion Are Involved in Src-MAPK-dependent Signaling in Human Ovarian Cancer Cells

Tanaka

Kobayashi

Suzuki

et al. 2004

Journal of Biological Chemistry

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“…It is interesting to note that TGF b 1 , which shares the same receptors with TGF b 2 , downregulates Src family tyrosine kinase activity in PC3 cells . In addition, in rat ®broblasts TGF b 1 signi®cantly decreased Src kinase activity and protein abundance, mainly by accelerating Src degradation (Fukuda et al, 1998). The tyrosine receptor induced Ras-MAPK pathway has been shown to be essential for cell proliferation (Ponzetto et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor β2 inhibition of Hepatocyte Growth Factor-induced endothelial proliferation and migration

Manganini

Maier

2000

Oncogene

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Angiogenesis is a highly controlled event which depends on the proper equilibrium of activators and inhibitors present within the microenvironment. Hepatocyte Growth Factor (HGF) activates migration and proliferation of endothelial cells and is angiogenic, acting through the tyrosine kinase receptor encoded by the Met protooncogene. To get insights into the molecular mechanisms involved in HGF-induced angiogenesis, we searched for cDNAs di erentially expressed in human endothelial cells exposed to HGF, a potent angiogenic factor. We found that HGF-treated endothelial cells upregulated the expression of Transforming Growth Factor (TGF) b 2 . To understand the signi®cance of this ®nding, we cultured endothelial cells with HGF and TGF b 2 simultaneously. We found that TGF b 2 impairs HGFdependent proliferative and migratory responses. TGF b 2 did not prevent the tyrosine phosphorylation of Met, but it inhibited some signalling pathways activated by HGF. We show that endothelial proliferation induced by HGF required the activation of the MAPK cascade, while HGF-induced endothelial migration was dependent on the tyrosine phosphorylation of Src. Indeed, TGF b 2 inhibited HGF e ects because it prevented HGF-induced MAP kinase activation and tyrosine phosphorylation of Src. We suggest that the induction of TGF b 2 by HGF in endothelial cells may represent a physiologic mechanism to counterbalance HGF angiogenic activity. Oncogene (2000) 19, 124 ± 133.

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“…This suggests that TGF-␤ 1 regulates Src protein levels mainly by modulating protein degradation rather than protein synthesis, consis- tent with the previous report suggesting the existence of a Src-specific degradation mechanism. 23,24 Several lines of evidence have suggested a relationship between TGF-␤s and Ras. For example, TGF-␤ 1 treatment caused a rapid increase in activated Ras in several cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we have reported that TGF-␤ 1 induces degradation of activated Src tyrosine kinase in rat fibroblasts. 23 In this study, to elucidate the alteration in the signaling pathway in TGF-␤ 1 -insensitive hepatoma cells, we compared the effect of TGF-␤ 1 on Src kinase in two human hepatoma cell lines that differ in their responsiveness to TGF-␤ 1 .…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we have reported that TGF-␤ 1 , a prototype of the TGF-␤ family, induces degradation of activated Src tyrosine kinase in rat fibroblasts. 23 TGF-␤ 1 also down-regulates Src-family protein tyrosine kinases in a human prostatic carcinoma cell line, PC 3. 24 These observations suggest that the Src kinase is involved in the TGF-␤ signaling pathway.…”

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confidence: 99%

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Altered regulation of Src tyrosine kinase by transforming growth factor β1 in a human hepatoma cell line

et al. 1998

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Transforming growth factor βs (TGF‐βs) are the potent growth inhibitors for various cell types. Certain transformed cells, however, show poor response to TGF‐β–induced growth inhibition, which contributes to their uncontrolled proliferation. Recently, we have reported that TGF‐β1 induces degradation of activated Src tyrosine kinase in rat fibroblasts. To elucidate the alteration in TGF‐β signaling pathway in tumor cells that cannot respond to the cytokine, we compared the effects of TGF‐β1 on Src kinase in two human hepatoma cell lines, TGF‐β1–insensitive Mahlavu cells and TGF‐β1–sensitive HepG2 cells. TGF‐β1 decreased Src kinase activity in HepG2 cells, but increased cellular Src levels and Src kinase activity in Mahlavu cells. Co‐incubation of Mahlavu cells with TGF‐β1 and 12‐O‐tetradecanoyl phorbol 13‐acetate (TPA) decreased Src protein levels and Src kinase activity, inducing TGF‐β1sensitivity. TGF‐β1 induced tyrosine dephosphorylation of Ras guanosine triphosphatase–activating protein (Ras‐GAP) and Ras inactivation in HepG2 cells, but induced Ras‐GAP phosphorylation and Ras activation in Mahlavu cells. The Src kinase inhibitor abolished the increase of Src kinase activity in TGF‐β1–treated Mahlavu cells, and induced TGF‐β1 sensitivity. These findings suggest that regulation of Src kinase by TGF‐β1is altered in Mahlavu cells. The altered regulation of Src may contribute to TGF‐β1 insensitivity in this cell line, at least in part through activation of Ras.

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Transforming growth factor-β1-induced degradation of activated Src tyrosine kinase in rat fibroblasts

Cited by 16 publications

References 28 publications

Transforming Growth Factor-β1-dependent Urokinase Up-regulation and Promotion of Invasion Are Involved in Src-MAPK-dependent Signaling in Human Ovarian Cancer Cells

Transforming Growth Factor-β1-dependent Urokinase Up-regulation and Promotion of Invasion Are Involved in Src-MAPK-dependent Signaling in Human Ovarian Cancer Cells

Transforming Growth Factor β2 inhibition of Hepatocyte Growth Factor-induced endothelial proliferation and migration

Altered regulation of Src tyrosine kinase by transforming growth factor β1 in a human hepatoma cell line

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