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TGF-β activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN

Nature Cell Biology volume 11, pages 881–889 (2009)Cite this article

Abstract

Akt kinase is activated by transforming growth factor-β1 (TGF-β) in diabetic kidneys, and has important roles in fibrosis, hypertrophy and cell survival in glomerular mesangial cells1,2,3,4,5,6,7,8,9,10,11. However, the mechanisms of Akt activation by TGF-β are not fully understood. Here we show that TGF-β activates Akt in glomerular mesangial cells by inducing the microRNAs (miRNAs) miR-216a and miR-217, both of which target PTEN (phosphatase and tensin homologue), an inhibitor of Akt activation. These miRNAs are located within the second intron of a non-coding RNA (RP23-298H6.1-001). The RP23 promoter was activated by TGF-β and miR-192 through E-box-regulated mechanisms, as shown previously3. Akt activation by these miRs led to glomerular mesangial cell survival and hypertrophy, which were similar to the effects of activation by TGF-β. These studies reveal a mechanism of Akt activation through PTEN downregulation by two miRs, which are regulated by upstream miR-192 and TGF-β. Due to the diversity of PTEN function12,13, this miR-amplifying circuit may have key roles, not only in kidney disorders, but also in other diseases.

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Figure 1: Expression and genomic organization of miR-216a and miR-217.
Figure 2: Pten is a direct target of miR-216a and miR-217.
Figure 3: Effects of miRNA inhibitors on downstream signalling in vitro and in vivo.
Figure 4: Effects of miR-192 and miR-216a/217 on Akt downstream targets.
Figure 5: Effects of miR-192 and miR-216a + 217 on FoxO3a activity, MMCs apoptosis and hypertrophy.

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Acknowledgements

This work was supported by grants from the NIH-National Institute of Diabetes and Digestive and Kidney Diseases and the Juvenile Diabetes Research Foundation (to RN). We are grateful to M. C.-T. Hu for a generous gift of plasmids (pFRE–Luc and FoxO3a–GFP), L.Wang and J. Arizala for technical assistance and S. DaCosta for editing the manuscript.

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Authors and Affiliations

  1. Gonda Diabetes Center, Beckman Research Institute of the City of Hope, Duarte, 91010, CA, USA

    Mitsuo Kato, Sumanth Putta, Mei Wang, Hang Yuan, Linda Lanting, Indu Nair, Ivan Todorov & Rama Natarajan

  2. Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, 91010, CA, USA

    Sumanth Putta, Amanda Gunn, John J. Rossi & Rama Natarajan

  3. Division of Molecular Biology, Beckman Research Institute of the City of Hope, Duarte, 91010, CA, USA

    John J. Rossi

  4. Department of Internal Medicine, Metabolism and Endocrinology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan

    Yoshimi Nakagawa & Hitoshi Shimano

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  1. Mitsuo Kato
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Contributions

M.K. and R.N. designed research; M.K., S.P., M.W., H.Y., L.L., I.N., A.G., and I.T. performed research; M.K., M.W., Y.N, H.S. and J.J.R. contributed new reagents/analytic tools; M.K., S.P. and I.T. analysed data and M.K. and R.N. wrote the paper.

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Correspondence to Mitsuo Kato or Rama Natarajan.

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Kato, M., Putta, S., Wang, M. et al. TGF-β activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN. Nat Cell Biol 11, 881–889 (2009). https://doi.org/10.1038/ncb1897

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