Role of β isoform of protein kinase C in hepatocyte growth factor-induced signal transduction in pigment cells

• Project/Area Number: 15591177
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: Kobe University
• Principal Investigator: OKA Masahiro Kobe University, Kobe University hospital, Associate Professor, 医学部附属病院, 講師 (30252761)
• Co-Investigator(Kenkyū-buntansha): MUKAI Hideyuki Kobe University, Biosignal Research Center, Associate Professor, バイオシグナル研究センター, 助教授 (80252758)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: hepatocyte growth factor / protein kinase C / malignant melanoma / phosphatidylinositol 3-kinase / phosphorylation / Gab1 / 色素細胞 / シグナル伝達 / アデノウイルスベクター

Research Abstract

The signaling pathway of hepatocyte growth factor (HGF) through its receptor-tyrosine kinase c-Met was examined in human normal melanocytes and malignant melanoma cell lines. HGF-induced c-Met activation was observed in both melanocytes and melanoma cells, whereas phosphatidylinositol 3-kinase (PI3K), a downstream target of c-Met, was not activated in the melanocytes but enhanced in the melanoma cells. Therefore, the role of Gab1, the scaffolding adapter protein that couples activated c-Met and PI3K, was analyzed in these cells. Gab1 in the melanocytes showed an electrophoretic mobility slower than that of the melanoma cells, and the mobility shifted to that of the melanoma cells after the treatment with alkaline phosphatase, indicating that Gab1 is highly phosphorylated on serine and threonine in the melanocytes. Introuction of protein kinase C (PKC) βII in the melanoma cells using adenovirus vector, that is expressed in the melanocytes but is absent in the melanoma cells, resulted in serine and threonine phosphorylation of Gab1. Furthermore, the introduction of PKCβII suppressed HGF-induced activation of Pl3K. These results indicate that the HGF signaling process from Gab1 to PI3K is negatively regulated by PKCβII.

Research Products

• [Journal Article] In vivo elimination of CD25+ regulatory T cells leads to tumor rejection of B16F10 melanoma, when combined with interleukin-12 gene transfer. (2004)
  • Author(s): Nagai, H., Horikawa, T., Hara, I., Fukunaga, A., Oniki, S., Oka, M., Nishigori, C., Ichihashi, M.
  • Journal Title: Exp.Dermatol. 13(10) Pages: 613-620
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fatty acids regulate pigmentation via proteosomal degradation of tyrosinase -A new aspect of ubiquitin-proteasome function. (2004)
  • Author(s): Ando, H., Watanabe, H., Valencia, J.C., Yasumoto, K., Furumura, M., Funasaka, Y., Oka, M., Ichihashi, M., Hearing, V.J.
  • Journal Title: J.Biol.Chem. 279(15) Pages: 15427-15433
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Down-regulation of melanogenesis by phospholipase D2 through ubiquitin proteasome-mediated degradation of tyrosinase. (2004)
  • Author(s): Kageyama, A., Oka, M., Okada, T, Nakamura, S., Ueyama, T., Saito, N., Hearing, V.J., Ichihashi, M., Nishigori, C.
  • Journal Title: J.Biol.Chem. 279(26) Pages: 27774-27780
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Phosphatidylinositol 3-kinase/Akt-dependent and -independent protection against apoptosis in normal human melanocytes. (2004)
  • Author(s): Oka, M., Kageyama, A., Fukunaga M., Bito T., Nagai H., Nishigori C.
  • Journal Title: J.Invest.Dermatol. 123(5) Pages: 930-936
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fatty acids regulate pigmentation via proteosomal degradation of tyrosinase - A new aspect of ubiquitin-proteasome function. (2004)
  • Author(s): Ando, H.他
  • Journal Title: J.Biol.Chem. 279・15 Pages: 15427-15433
• [Journal Article] Down-regulation of melanogenesis by phospholipase D2 through ubiquitin proteasome-mediated degradation of tyrosinase (2004)
  • Author(s): Kageyama, A.他
  • Journal Title: J.Biol.Chem. 279・26 Pages: 27774-27780
• [Journal Article] Phosphatidylinositol 3-kinase/Akt-dependent and -independent protection against apoptosis in normal human melanocytes. (2004)
  • Author(s): Oka, M.他
  • Journal Title: J.Invest.Dermatol. 123・6 Pages: 930-936
• [Journal Article] In viva elimination of CD25+ regulatory T cells leads to tumor rejection of B16F10 melanoma, when combined with interleukin-12 gene transfer. (2004)
  • Author(s): Nagai, H.他
  • Journal Title: Exp.Dermatol. 13・10 Pages: 613-620
• [Journal Article] Regulation of notchl and d114 by vascular endothelial growth factor in arterial endotlial cells : implications for modulating arteriogenesis and angiogenosis. (2003)
  • Author(s): Liu, Z.J. 他
  • Journal Title: Mol.Cell.Biol. 23 Pages: 14-25
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Differential response of primary and metastatic melanomas to neutrophils at racted by IL-8. (2003)
  • Author(s): Schaider, H. 他
  • Journal Title: Int.J.Cancer 103 Pages: 335-343
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Stroma formation and angiogenesis by overexpression of growth factors, cytoines, and proteolytic enzymes in human skin grafted to SCID mice. (2003)
  • Author(s): Gruss, C.J. 他
  • Journal Title: J.Invest.Dermatol. 120 Pages: 683-692
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Protein Kinase C α Associates with Phospholipase D1 and Enhances Basal Phospholipase D Activity in Protein Phosphorylation-Independent Manner in Human Melanoma Cells (2003)
  • Author(s): Oka, M. 他
  • Journal Title: J.Invest.Dermatol. 121 Pages: 69-76
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Reciprocal regulation of MelCAM and AKT in human melanoma. (2003)
  • Author(s): Li, G. 他
  • Journal Title: Oncogene 22 Pages: 6891-6899
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] PKCδ inhibits PKCα-mediated activation of PLD1 in a manner independent of its protein kinase activity. (2003)
  • Author(s): Oka, M. 他
  • Journal Title: FEBS Letters 554 Pages: 179-183
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of notch1 and dll4 by vascular endothelial growth factor in arterial endothelial cells : implications for modulating arteriogenesis and angiogenesis. (2003)
  • Author(s): Liu, Z.J., Shirakawa, T., Li, Y., Soma, A., Oka, M., Dotto, G.P., Fairman, R.M., Velazquez, O.C., Herlyn, M.
  • Journal Title: Mol.Cell.Biol. 23(1) Pages: 14-25
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Differential response of primary and metastatic melanomas to neutrophils attracted by IL-8. (2003)
  • Author(s): Schaider, H., Oka, M., Bogenrieder, T., Nesbit, M., Satyamoorthy, K., Berking, C., Matsushima, K., Herlyn, M.
  • Journal Title: Int.J.Cancer 103(3) Pages: 335-343
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Stroma formation and angiogenesis by overexpression of growth factors, cytokines, and proteolytic enzymes in human skin grafted to SCID mice. (2003)
  • Author(s): Gruss, C.J., Satyamoorthy, K., Berking, C., Lininger, J., Nesbit, M., Schaider, H., Liu, Z-J., Oka, M., Hsu, M-Y., Shirakawa, T., Li, G., Carmeliet, P., EI-Deiry, W.S., Eck.S.L., Rao, J.S., Baker, A.H., Bennet, J.D., Crombleholme, T.M., Margolis, D.J., Wilson, J.M., Werner, S., Detmar, M., Skobe, M., Robbins, P.D., Johnson, C., Carbone, D., Buck, Clayton., Herlyn, M.
  • Journal Title: J.Invest.Dermatol. 120(4) Pages: 683-692
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Protein kinase C α associates with phospholipase D1 and enhances basal phospholipase D activity in a protein phosphorylation-independent manner in human melanoma cells. (2003)
  • Author(s): Oka, M., Kageshita, T., Ono, T., Goto, A., Kuroki, T, Ichihashi, M.
  • Journal Title: J.Invest.Dermatol. 121(1) Pages: 69-76
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Reciprocal regulation of MelCAM and AKT in human melanoma. (2003)
  • Author(s): Li, G., Kalabis, J., Xu, X., Meier, F., Oka, M., Bogenrieder, T., Herlyn, M.
  • Journal Title: Oncogene 22(44) Pages: 6891-6899
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] PKCδ inhibits PKCα-mediated activation of PLD1 in a manner independent of its protein kinase activity. (2003)
  • Author(s): Oka, M., Okada, T., Nakamura, S., Ohba, M., Kuroki, T., Kikkawa, U., Nagai, H., Ichihashi, M., Nishigori, C.
  • Journal Title: FEBS Letters 554(1-2) Pages: 179-183
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Oka, M., Kageshita, T., Ono, T., Goto, A., Kuroki, T., Ichihashi, M.: "Protein Kinase C α Associates with Phospholipase D1 and Enhances Basal Phospholipase D Activity in a Protein Phosphorylation-Independent Manner in Human Melanoma Cells"J.Invest.Dermatol.. 121・1. 69-76 (2003)
• [Publications] Li, G., Kalabis, J., Xu, X., Meier, F., Oka, M., Bogenrieder, T., Herlyn, M.: "Reciprocal regulation of MelCAM and AKT in human melanoma"Oncogene. 22・44. 6891-6899 (2003)
• [Publications] Oka, M., Okada, T., Nakamura, S., Ohba, M., Kuroki, T., Kikkawa, U., Nagai, H., Ichihashi, M., Nishigori, C.: "PKCδ inhibits PKCα-mediated activation of PLD1 in a manner independent of its protein kinase activity"FEBS Letters. 554・1-2. 179-183 (2003)