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TGF-β and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions

Oncogene volume 23, pages 7416–7429 (2004)Cite this article

Abstract

Although hepatocyte growth factor (HGF) can act synergistically or antagonistically with transforming growth factor-β (TGF-β) signaling, molecular mechanism of their crosstalk remains unknown. Using antibodies which selectively distinguished receptor-regulated Smads (R-Smads) phosphorylated at linker regions from those at C-terminal regions, we herein showed that either HGF or TGF-β treatment of normal stomach-origin cells activated the JNK pathway, thereafter inducing endogenous R-Smads phosphorylation at linker regions. However, the phosphorylation at their C-terminal regions was not induced by HGF treatment. The activated JNK could directly phosphorylate R-Smads in vitro at the same sites that were phosphorylated in response to TGF-β or HGF in vivo. Thus, the linker regions of R-Smads were the common phosphorylation sites for HGF and TGF-β signaling pathways. The phosphorylation induced by simultaneous treatment with HGF and TGF-β allowed R-Smads to associate with Smad4 and to translocate into the nucleus. JNK pathway involved HGF and TGF-β-mediated infiltration potency since a JNK inhibitor SP600125 caused the reduction of invasive capacity induced by HGF and TGF-β signals. Moreover, a combined treatment with HGF and TGF-β led to a potent increase in plasminogen activator inhibitor type 1 transcriptional activity through Smad3 phosphorylation at the linker region. In contrast, HGF treatment reduced TGF-β-dependent activation of p15INK4B promoter, in which Smad3 phosphorylation at the C-terminal region was involved. In conclusion, HGF and TGF-β transmit the signals through JNK-mediated R-Smads phosphorylation at linker regions.

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Abbreviations

ERK:

extracellular signal-regulated kinase

JNK:

c-Jun N-terminal kinase

MAPK:

mitogen-activated protein kinase

MEKK-1:

mitogen-activated protein kinase kinase kinase-1

PAI-1:

plasminogen activator inhibitor type 1

R-Smads:

receptor-regulated Smads

SAPK:

stress-activated protein kinase

TAK1:

TGF-β-activated kinase 1

TβRI:

TGF-β type I receptor

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Acknowledgements

We would like to thank Dr R Derynck (University of California at San Francisco) and Dr S Ohno (Yokohama City University School of Medicine) for providing us with cDNAs encoding human Smad2 and Smad3 and with cDNA encoding dominant-negative form of MEKK-1, respectively. We are grateful to Dr X-F Wang (Duke University) and Drs P ten Dijke and C-H Heldin (Ludwig Institute for Cancer Research) for the generous gifts of p15P113-luc vector and (SBE)4-Luc vector, respectively. We also thank Dr AB Roberts (National Cancer Institute) for helpful discussions concerned with the study. This study was supported by a Grant-in-Aid for scientific research from the Ministry of Education, Science and Culture of Japan.

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Authors and Affiliations

  1. Third Department of Internal Medicine, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka, 570-8507, Japan

    Shigeo Mori, Koichi Matsuzaki, Katsunori Yoshida, Fukiko Furukawa, Yoshiya Tahashi, Hideo Yamagata, Go Sekimoto, Toshihito Seki & Kazuichi Okazaki

  2. Division of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba, 2-1-1 Amakubo, Tsukuba, 305-8576, Ibaraki, Japan

    Hirofumi Matsui

  3. RIKEN Cell Bank, The Institute of Chemistry and Physics (RIKEN), 3-1-1 Koyadai, Tsukuba, 305-0074, Ibaraki, Japan

    Hirofumi Matsui

  4. Department of Medical Chemistry, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka, 570-8507, Japan

    Mikio Nishizawa

  5. Department of Microbiology, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka, 570-8507, Japan

    Jun-ichi Fujisawa

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  1. Shigeo Mori
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Correspondence to Koichi Matsuzaki.

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Mori, S., Matsuzaki, K., Yoshida, K. et al. TGF-β and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions. Oncogene 23, 7416–7429 (2004). https://doi.org/10.1038/sj.onc.1207981

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