Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis

T. Ayada, K. Taniguchi, F. Okamoto, R. Kato, S. Komune, G. Takaesu, Akihiko Yoshimura

研究成果: Article

23 引用 (Scopus)

抄録

Sproutys have been shown to negatively regulate growth factor-induced extracellular signal-regulated kinase (ERK) activation, and suggested to be an anti-oncogene. However, molecular mechanism of the suppression has not yet been clarified completely. Sprouty4 inhibits vascular endothelial growth factor (VEGF)-A-induced ERK activation, but not VEGF-C-induced ERK activation. It has been shown that VEGF-A-mediated ERK activation is strongly dependent on protein kinase C (PKC), whereas that by VEGF-C is dependent on Ras. This suggests that Sprouty4 inhibits the PKC pathway more specifically than the Ras pathway. In this study, we confirmed that Sprouty4 suppressed various signals downstream of PKC, such as phosphorylation of MARCKS and protein kinase D (PKD), as well as PKC-dependent nuclear factor (NF)-κB activation. Furthermore, Sprouty4 suppressed upstream signals of PKC, such as Ca2+ mobilization, phosphatidylinositol 4,5-biphosphate (PIP2) breakdown and inositol 1,4,5-triphosphate (IP3) production in response to VEGF-A. Those effects were dependent on the C-terminal cysteine-rich region, but not on the N-terminal region of Sprouty4, which is critical for the suppression of fibroblast growth factor (FGF)-mediated ERK activation. Sprouty4 overexpression or deletion of the Sprouty4 gene did not affect phospholipase C (PLC) γ-1 activation, which is an enzyme that catalyzes PIP2 hydrolysis. Moreover, Sprouty4 inhibited not only VEGF-A-mediated PIP2 hydrolysis but also inhibited the lysophosphatidic acid (LPA)-induced PIP2 breakdown that is catalyzed by PLCβ/ε activated by G-protein coupled receptor (GPCR). Taken together, Sprouty4 has broader suppression activity for various stimuli than previously thought; it may function as an inhibitor for various types of PLC-dependent signaling as well as for ERK activation.

元の言語English
ページ(範囲)1076-1088
ページ数13
ジャーナルOncogene
28
発行部数8
DOI
出版物ステータスPublished - 2009 2 26

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Phosphatidylinositol 4,5-Diphosphate
Extracellular Signal-Regulated MAP Kinases
Protein Kinase C
Hydrolysis
Vascular Endothelial Growth Factor A
Type C Phospholipases
Vascular Endothelial Growth Factor C
Inositol 1,4,5-Trisphosphate
Fibroblast Growth Factors
Gene Deletion
G-Protein-Coupled Receptors
Tumor Suppressor Genes
Cysteine
Intercellular Signaling Peptides and Proteins
Phosphorylation
Enzymes

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

これを引用

Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis. / Ayada, T.; Taniguchi, K.; Okamoto, F.; Kato, R.; Komune, S.; Takaesu, G.; Yoshimura, Akihiko.

:: Oncogene, 巻 28, 番号 8, 26.02.2009, p. 1076-1088.

研究成果: Article

Ayada, T. ; Taniguchi, K. ; Okamoto, F. ; Kato, R. ; Komune, S. ; Takaesu, G. ; Yoshimura, Akihiko. / Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis. :: Oncogene. 2009 ; 巻 28, 番号 8. pp. 1076-1088.
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abstract = "Sproutys have been shown to negatively regulate growth factor-induced extracellular signal-regulated kinase (ERK) activation, and suggested to be an anti-oncogene. However, molecular mechanism of the suppression has not yet been clarified completely. Sprouty4 inhibits vascular endothelial growth factor (VEGF)-A-induced ERK activation, but not VEGF-C-induced ERK activation. It has been shown that VEGF-A-mediated ERK activation is strongly dependent on protein kinase C (PKC), whereas that by VEGF-C is dependent on Ras. This suggests that Sprouty4 inhibits the PKC pathway more specifically than the Ras pathway. In this study, we confirmed that Sprouty4 suppressed various signals downstream of PKC, such as phosphorylation of MARCKS and protein kinase D (PKD), as well as PKC-dependent nuclear factor (NF)-κB activation. Furthermore, Sprouty4 suppressed upstream signals of PKC, such as Ca2+ mobilization, phosphatidylinositol 4,5-biphosphate (PIP2) breakdown and inositol 1,4,5-triphosphate (IP3) production in response to VEGF-A. Those effects were dependent on the C-terminal cysteine-rich region, but not on the N-terminal region of Sprouty4, which is critical for the suppression of fibroblast growth factor (FGF)-mediated ERK activation. Sprouty4 overexpression or deletion of the Sprouty4 gene did not affect phospholipase C (PLC) γ-1 activation, which is an enzyme that catalyzes PIP2 hydrolysis. Moreover, Sprouty4 inhibited not only VEGF-A-mediated PIP2 hydrolysis but also inhibited the lysophosphatidic acid (LPA)-induced PIP2 breakdown that is catalyzed by PLCβ/ε activated by G-protein coupled receptor (GPCR). Taken together, Sprouty4 has broader suppression activity for various stimuli than previously thought; it may function as an inhibitor for various types of PLC-dependent signaling as well as for ERK activation.",
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T1 - Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis

AU - Ayada, T.

AU - Taniguchi, K.

AU - Okamoto, F.

AU - Kato, R.

AU - Komune, S.

AU - Takaesu, G.

AU - Yoshimura, Akihiko

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AB - Sproutys have been shown to negatively regulate growth factor-induced extracellular signal-regulated kinase (ERK) activation, and suggested to be an anti-oncogene. However, molecular mechanism of the suppression has not yet been clarified completely. Sprouty4 inhibits vascular endothelial growth factor (VEGF)-A-induced ERK activation, but not VEGF-C-induced ERK activation. It has been shown that VEGF-A-mediated ERK activation is strongly dependent on protein kinase C (PKC), whereas that by VEGF-C is dependent on Ras. This suggests that Sprouty4 inhibits the PKC pathway more specifically than the Ras pathway. In this study, we confirmed that Sprouty4 suppressed various signals downstream of PKC, such as phosphorylation of MARCKS and protein kinase D (PKD), as well as PKC-dependent nuclear factor (NF)-κB activation. Furthermore, Sprouty4 suppressed upstream signals of PKC, such as Ca2+ mobilization, phosphatidylinositol 4,5-biphosphate (PIP2) breakdown and inositol 1,4,5-triphosphate (IP3) production in response to VEGF-A. Those effects were dependent on the C-terminal cysteine-rich region, but not on the N-terminal region of Sprouty4, which is critical for the suppression of fibroblast growth factor (FGF)-mediated ERK activation. Sprouty4 overexpression or deletion of the Sprouty4 gene did not affect phospholipase C (PLC) γ-1 activation, which is an enzyme that catalyzes PIP2 hydrolysis. Moreover, Sprouty4 inhibited not only VEGF-A-mediated PIP2 hydrolysis but also inhibited the lysophosphatidic acid (LPA)-induced PIP2 breakdown that is catalyzed by PLCβ/ε activated by G-protein coupled receptor (GPCR). Taken together, Sprouty4 has broader suppression activity for various stimuli than previously thought; it may function as an inhibitor for various types of PLC-dependent signaling as well as for ERK activation.

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