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Angiogenesis

, Volume 21, Issue 2, pp 415–423 | Cite as

Serum/glucocorticoid-regulated kinase 1 as a novel transcriptional target of bone morphogenetic protein-ALK1 receptor signaling in vascular endothelial cells

  • Mutsumi Araki
  • Takashi Hisamitsu
  • Yumi Kinugasa-Katayama
  • Toru Tanaka
  • Yukihiro Harada
  • Shu Nakao
  • Sanshiro Hanada
  • Shuhei Ishii
  • Masahide Fujita
  • Teruhisa Kawamura
  • Yoshihiko Saito
  • Koichi Nishiyama
  • Yusuke Watanabe
  • Osamu Nakagawa
Brief Communication
  • 406 Downloads

Abstract

Bone morphogenetic protein 9 (BMP9)/BMP10-ALK1 receptor signaling is essential for endothelial differentiation and vascular morphogenesis. Mutations in ALK1/ACVRL1 and other signal-related genes are implicated in human vascular diseases, and the Alk1/Acvrl1 deletion in mice causes severe impairment of vascular formation and embryonic lethality. In the microarray screen to search for novel downstream genes of ALK1 signaling, we found that the mRNA and protein expression of serum/glucocorticoid-regulated kinase 1 (SGK1) was rapidly up-regulated by the BMP9 stimulation of cultured human endothelial cells. The increase in SGK1 mRNA was completely blocked by the transcriptional inhibitor actinomycin D and significantly suppressed by the siRNA treatment against the co-SMAD transcription factor SMAD4. Upon the BMP9 treatment of endothelial cells, phosphorylated SMAD1/5/9 bound to a consensus site upstream of the SGK1 gene, which was necessary for BMP9-dependent increment of the luciferase reporter activity driven by the SGK1 proximal enhancer. The Sgk1 mRNA expression in mouse embryos was enriched in vascular endothelial cells at embryonic day 9.0–9.5, at which Sgk1 null mice showed embryonic lethality due to abnormal vascular formation, and its mRNA as well as protein expression was clearly reduced in Alk1/Acvrl1 null embryos. These results indicate that SGK1 is a novel target gene of BMP9/BMP10-ALK1 signaling in endothelial cells and further suggest a possibility that down-regulation of the Sgk1 expression may be involved in the mechanisms of vascular defects by the ALK1 signaling deficiency.

Keywords

ALK1 signaling Bone morphogenetic protein Endothelial cell Serum/glucocorticoid-regulated kinase 1 Transcriptional regulation Vascular development 

Notes

Acknowledgements

The authors thank T. Tsujiuchi and N. Kurumatani for general instruction, K. Miyazono, T. Watabe, F. Itoh, M. Okada, S. Nada and T. Akagi for information and reagents, T. Ioka, M. Sakabe, T. Uemoto, H. Kawakami, N. Yoshida, M. Suzuki and K. Endo for technical instruction and assistance. This work was supported in part by the grants from the Ministry of Education, Culture, Sports, Science and Technology, Takeda Science Foundation, SENSIN Medical Research Foundation, The Smoking Research Foundation and Miyata Cardiac Research Promotion Foundation, the Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center, and Nara Medical University Grant-in-Aid for Collaborative Research Projects.

Supplementary material

10456_2018_9605_MOESM1_ESM.pdf (96 kb)
Supplementary material 1 (PDF 95 kb)

References

  1. 1.
    Herbert SP, Stainier DY (2011) Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat Rev Mol Cell Biol 12(9):551–564CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146(6):873–887CrossRefPubMedGoogle Scholar
  3. 3.
    Miyazono K, Kamiya Y, Morikawa M (2010) Bone morphogenetic protein receptors and signal transduction. J Biochem 147(1):35–51CrossRefPubMedGoogle Scholar
  4. 4.
    Cai J et al (2012) BMP signaling in vascular diseases. FEBS Lett 586(14):1993–2002CrossRefPubMedGoogle Scholar
  5. 5.
    Garcia de Vinuesa A et al (2016) BMP signaling in vascular biology and dysfunction. Cytokine Growth Factor Rev 27:65–79CrossRefPubMedGoogle Scholar
  6. 6.
    Urness LD, Sorensen LK, Li DY (2000) Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet 26(3):328–331CrossRefPubMedGoogle Scholar
  7. 7.
    Oh SP et al (2000) Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci USA 97(6):2626–2631CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Li DY et al (1999) Defective angiogenesis in mice lacking endoglin. Science 284(5419):1534–1537CrossRefPubMedGoogle Scholar
  9. 9.
    Tillet E, Bailly S (2014) Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia. Front Genet 5:456PubMedGoogle Scholar
  10. 10.
    Ma L, Chung WK (2017) The role of genetics in pulmonary arterial hypertension. J Pathol 241(2):273–280CrossRefPubMedGoogle Scholar
  11. 11.
    Webster MK et al (1993) Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. Mol Cell Biol 13(4):2031–2040CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Waldegger S et al (1997) Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume. Proc Natl Acad Sci USA 94(9):4440–4445CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Di Cristofano A (2017) SGK1: the dark side of PI3K signaling. Curr Top Dev Biol 123:49–71CrossRefPubMedGoogle Scholar
  14. 14.
    Yang M et al (2012) Serum-glucocorticoid regulated kinase 1 regulates alternatively activated macrophage polarization contributing to angiotensin II-induced inflammation and cardiac fibrosis. Arterioscler Thromb Vasc Biol 32(7):1675–1686CrossRefPubMedGoogle Scholar
  15. 15.
    Borst O et al (2015) Pivotal role of serum- and glucocorticoid-inducible kinase 1 in vascular inflammation and atherogenesis. Arterioscler Thromb Vasc Biol 35(3):547–557CrossRefPubMedGoogle Scholar
  16. 16.
    Zarrinpashneh E et al (2013) Ablation of SGK1 impairs endothelial cell migration and tube formation leading to decreased neo-angiogenesis following myocardial infarction. PLoS ONE 8(11):e80268CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Catela C et al (2010) Serum and glucocorticoid-inducible kinase 1 (SGK1) is necessary for vascular remodeling during angiogenesis. Dev Dyn 239(8):2149–2160CrossRefPubMedGoogle Scholar
  18. 18.
    David L et al (2007) Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 109(5):1953–1961CrossRefPubMedGoogle Scholar
  19. 19.
    Suzuki Y et al (2010) BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo. J Cell Sci 123(Pt 10):1684–1692CrossRefPubMedGoogle Scholar
  20. 20.
    Morikawa M et al (2011) ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif. Nucleic Acids Res 39(20):8712–8727CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Larrivée B et al (2012) ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway. Dev Cell 22(3):489–500CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kobayashi T et al (1999) Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase. Biochem J 344(Pt 1):189–197CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    David L et al (2008) Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ Res 102(8):914–922CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Herrera B et al (2009) Autocrine bone morphogenetic protein-9 signals through activin receptor-like kinase-2/Smad1/Smad4 to promote ovarian cancer cell proliferation. Cancer Res 69(24):9254–9262CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Nakagawa O et al (2000) Members of the HRT family of basic helix-loop-helix proteins act as transcriptional repressors downstream of Notch signaling. Proc Natl Acad Sci USA 97(25):13655–13660CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Somekawa S et al (2012) Tmem100, an ALK1 receptor signaling-dependent gene essential for arterial endothelium differentiation and vascular morphogenesis. Proc Natl Acad Sci USA 109(30):12064–12069CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Heldin CH, Moustakas A (2012) Role of Smads in TGFbeta signaling. Cell Tissue Res 347(1):21–36CrossRefPubMedGoogle Scholar
  28. 28.
    Brickley DR et al (2002) Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1 (SGK-1). J Biol Chem 277(45):43064–43070CrossRefPubMedGoogle Scholar
  29. 29.
    Mori S et al (2014) The mTOR pathway controls cell proliferation by regulating the FoxO3a transcription factor via SGK1 kinase. PLoS ONE 9(2):e88891CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Arteaga MF et al (2007) Multiple translational isoforms give functional specificity to serum- and glucocorticoid-induced kinase 1. Mol Biol Cell 18(6):2072–2080CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Simon P et al (2007) Differential regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) splice variants based on alternative initiation of transcription. Cell Physiol Biochem 20(6):715–728CrossRefPubMedGoogle Scholar
  32. 32.
    Arteaga MF et al (2008) A brain-specific SGK1 splice isoform regulates expression of ASIC1 in neurons. Proc Natl Acad Sci USA 105(11):4459–4464CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Korchynskyi O, ten Dijke P (2002) Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J Biol Chem 277(7):4883–4891CrossRefPubMedGoogle Scholar
  34. 34.
    Lee E, Lein ES, Firestone GL (2001) Tissue-specific expression of the transcriptionally regulated serum and glucocorticoid-inducible protein kinase (Sgk) during mouse embryogenesis. Mech Dev 103(1–2):177–181CrossRefPubMedGoogle Scholar
  35. 35.
    Zhang YE (2017) Non-Smad signaling pathways of the TGF-beta family. Cold Spring Harb Perspect Biol 9(2):a022129CrossRefPubMedGoogle Scholar
  36. 36.
    Waldegger S et al (1999) h-sgk serine-threonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine. Gastroenterology 116(5):1081–1088CrossRefPubMedGoogle Scholar
  37. 37.
    Lang F et al (2000) Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy. Proc Natl Acad Sci USA 97(14):8157–8162CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Schmidt S et al (2014) TGFbeta1 and SGK1-sensitive store-operated Ca2+ entry and Orai1 expression in endometrial Ishikawa cells. Mol Hum Reprod 20(2):139–147CrossRefPubMedGoogle Scholar
  39. 39.
    Seki T, Yun J, Oh SP (2003) Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. Circ Res 93(7):682–689CrossRefPubMedGoogle Scholar
  40. 40.
    Morikawa M et al (2013) Genome-wide mechanisms of Smad binding. Oncogene 32(13):1609–1615CrossRefPubMedGoogle Scholar
  41. 41.
    Shiojima I, Walsh K (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 90(12):1243–1250CrossRefPubMedGoogle Scholar
  42. 42.
    Kobayashi T, Cohen P (1999) Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem J 339(Pt 2):319–328CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Garcia-Martinez JM, Alessi DR (2008) mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 416(3):375–385CrossRefPubMedGoogle Scholar
  44. 44.
    Ola R et al (2016) PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia. Nat Commun 7:13650CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Mutsumi Araki
    • 1
    • 2
    • 3
  • Takashi Hisamitsu
    • 1
  • Yumi Kinugasa-Katayama
    • 1
  • Toru Tanaka
    • 1
  • Yukihiro Harada
    • 1
    • 4
  • Shu Nakao
    • 1
    • 4
  • Sanshiro Hanada
    • 6
  • Shuhei Ishii
    • 1
    • 2
  • Masahide Fujita
    • 1
    • 3
  • Teruhisa Kawamura
    • 4
  • Yoshihiko Saito
    • 2
    • 5
  • Koichi Nishiyama
    • 6
  • Yusuke Watanabe
    • 1
    • 2
  • Osamu Nakagawa
    • 1
    • 2
    • 3
  1. 1.Department of Molecular PhysiologyNational Cerebral and Cardiovascular Center Research InstituteSuitaJapan
  2. 2.Graduate School of Medical SciencesNara Medical UniversityKashihara, NaraJapan
  3. 3.Laboratory for Cardiovascular System ResearchNara Medical University Advanced Medical Research CenterKashihara, NaraJapan
  4. 4.Laboratory of Stem Cell and Regenerative Medicine, Department of Biomedical Sciences, College of Life SciencesRitsumeikan UniversityKusatsuJapan
  5. 5.The First Department of Internal MedicineNara Medical UniversityKashihara, NaraJapan
  6. 6.International Research Center for Medical SciencesKumamoto UniversityKumamotoJapan

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