Skip to main content
SpringerLink
Log in

FHA domain of AGGF1 is essential for its nucleocytoplasmic transport and angiogenesis

  • Research Paper
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

Angiogenic factor with G-patch and FHA domains 1 (AGGF1) exhibits a dynamic distribution from the nucleus to the cytoplasm in endothelial cells during angiogenesis, but the biological significance and underlying mechanism of this nucleocytoplasmic transport remains unknown. Here, we demonstrate that the dynamic distribution is essential for AGGF1 to execute its angiogenic function. To search the structural bases for this nucleocytoplasmic transport, we characterized three potential nuclear localization regions, one potential nuclear export region, forkhead-associated (FHA), and G-patch domains to determine their effects on nucleocytoplasmic transport and angiogenesis, and we show that AGGF1 remains intact during the dynamic subcellular distribution and the region from 260 to 288 amino acids acts as a signal for its nuclear localization. The distribution of AGGF1 in cytoplasm needs both FHA domain and 14-3-3α/β. Binding of AGGF1 via FHA domain to 14-3-3α/β is required to complete the transport. Thus, we for the first time established structural bases for the nucleocytoplasmic transport of AGGF1 and revealed that the FHA domain of AGGF1 is essential for its nucleocytoplasmic transport and angiogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Brown, A.K., and Webb, A.E. (2018). Regulation of FOXO factors in mammalian cells. Curr Top Dev Biol 127, 165–192.

    Article  CAS  PubMed  Google Scholar 

  • Chevalier, S.A., Meertens, L., Calattini, S., Gessain, A., Kiemer, L., and Mahieux, R. (2005). Presence of a functional but dispensable nuclear export signal in the HTLV-2 Tax protein. Retrovirology 2, 70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cook, A., Bono, F., Jinek, M., and Conti, E. (2007). Structural biology of nucleocytoplasmic transport. Annu Rev Biochem 76, 647–671.

    Article  CAS  PubMed  Google Scholar 

  • Deak, J.C., Cross, J.V., Lewis, M., Qian, Y., Parrott, L.A., Distelhorst, C. W., and Templeton, D.J. (1998). Fas-induced proteolytic activation and intracellular redistribution of the stress-signaling kinase MEKK1. Proc Natl Acad Sci USA 95, 5595–5600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Durocher, D., Smerdon, S.J., Yaffe, M.B., and Jackson, S.P. (2000). The FHA domain in DNA repair and checkpoint signaling. Cold Spring Harb Symp Quantitat Biol 65, 423–432.

    Article  CAS  Google Scholar 

  • Fei, H.R., Cui, L.Y., Zhang, Z.R., Zhao, Y., and Wang, F.Z. (2012). Caudatin inhibits carcinomic human alveolar basal epithelial cell growth and angiogenesis through modulating GSK3β/β-catenin pathway. J Cell Biochem 113, 3403–3410.

    Article  CAS  PubMed  Google Scholar 

  • Han, D.C., Shen, T.L., Miao, H., Wang, B., and Guan, J.L. (2002). EphB1 associates with Grb7 and regulates cell migration. J Biol Chem 277, 45655–45661.

    Article  CAS  PubMed  Google Scholar 

  • Hu, F.Y., Wu, C., Li, Y., Xu, K., Wang, W.J., Cao, H., and Tian, X.L. (2013). AGGF1 is a novel anti-inflammatory factor associated with TNF-α-induced endothelial activation. Cell Signal 25, 1645–1653.

    Article  CAS  PubMed  Google Scholar 

  • Kaffman, A., Rank, N.M., and O’Shea, E.K. (1998). Phosphorylation regulates association of the transcription factor Pho4 with its import receptor Pse1/Kap121. Genes Dev 12, 2673–2683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kashiwada, T., Fukuhara, S., Terai, K., Tanaka, T., Wakayama, Y., Ando, K., Nakajima, H., Fukui, H., Yuge, S., Saito, Y., et al. (2015). β-catenin-dependent transcription is central to Bmp-mediated formation of venous vessels. Development 142, 497–509.

    CAS  PubMed  Google Scholar 

  • Kumagai, A., and Dunphy, W.G. (1999). Binding of 14-3-3β proteins and nuclear export control the intracellular localization of the mitotic inducer Cdc25. Genes Dev 13, 1067–1072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar, S., Saradhi, M., Chaturvedi, N.K., and Tyagi, R.K. (2006). Intracellular localization and nucleocytoplasmic trafficking of steroid receptors: an overview. Mol Cell Endocrinol 246, 147–156.

    Article  CAS  PubMed  Google Scholar 

  • la Cour, T., Kiemer, L., Mølgaard, A., Gupta, R., Skriver, K., and Brunak, S. (2004). Analysis and prediction of leucine-rich nuclear export signals. Protein Eng Des Sel 17, 527–536.

    Article  CAS  PubMed  Google Scholar 

  • Lee, J.C., Kim, D.S., Moon, D.C., Lee, J.H., Kim, M.J., Lee, S.M., Lee, Y. S., Kang, S.W., Lee, E.J., Kang, S.S., et al. (2009). Prediction of bacterial proteins carrying a nuclear localization signal and nuclear targeting of HsdM from Klebsiella pneumoniae. J Microbiol 47, 641–645.

    Article  CAS  PubMed  Google Scholar 

  • Li, J., Lee, G.I., Van Doren, S.R., and Walker, J.C. (2000). The FHA domain mediates phosphoprotein interactions. J Cell Sci 113 Pt 23, 4143–4149.

    Article  Google Scholar 

  • Li, L., Chen, D., Li, J., Wang, X., Wang, N., Xu, C., and Wang, Q.K. (2014). AGGF1 acts at the top of the genetic regulatory hierarchy in specification of hemangioblasts in zebrafish. Blood 123, 501–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu, Q., Yao, Y., Yao, Y., Liu, S., Huang, Y., Lu, S., Bai, Y., Zhou, B., Xu, Y., Li, L., et al. (2012). Angiogenic factor AGGF1 promotes therapeutic angiogenesis in a mouse limb ischemia model. PLoS ONE 7, e46998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Major, M.B., Roberts, B.S., Berndt, J.D., Marine, S., Anastas, J., Chung, N., Ferrer, M., Yi, X.H., Stoick-Cooper, C.L., von Haller, P.D., et al. (2008). New regulators of Wnt/β-catenin signaling revealed by integrative molecular screening. Sci Signal 1, ra12.

    PubMed  Google Scholar 

  • Manning, B.D., and Cantley, L.C. (2007). AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montenarh, M. (2014). Protein kinase CK2 and angiogenesis. Adv Clin Exp Med 23, 153–158.

    Article  PubMed  Google Scholar 

  • Muslin, A.J., Tanner, J.W., Allen, P.M., and Shaw, A.S. (1996). Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell 84, 889–897.

    Article  CAS  PubMed  Google Scholar 

  • Muslin, A., and Xing, H.M. (2000). 14-3-3 proteins: regulation of subcellular localization by molecular interference. Cell Signal 12, 703–709.

    Article  CAS  PubMed  Google Scholar 

  • Nigg, E.A. (1997). Nucleocytoplasmic transport: signals, mechanisms and regulation. Nature 386, 779–787.

    Article  CAS  PubMed  Google Scholar 

  • Olsnes, S., Klingenberg, O., and Wiçdłocha, A. (2003). Transport of exogenous growth factors and cytokines to the cytosol and to the nucleus. Physiol Rev 83, 163–182.

    Article  CAS  PubMed  Google Scholar 

  • Planque, N. (2006). Nuclear trafficking of secreted factors and cell-surface receptors: new pathways to regulate cell proliferation and differentiation, and involvement in cancers. Cell Commun Signal 4, 7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rivière, Y., Blank, V., Kourilsky, P., and Israël, A. (1991). Processing of the precursor of NF-κB by the HIV-1 protease during acute infection. Nature 350, 625–626.

    Article  PubMed  Google Scholar 

  • Rousseau, A., and Bertolotti, A. (2018). Regulation of proteasome assembly and activity in health and disease. Nat Rev Mol Cell Biol 19, 697–712.

    Article  CAS  PubMed  Google Scholar 

  • Scott, M.S., Troshin, P.V., and Barton, G.J. (2011). NoD: a nucleolar localization sequence detector for eukaryotic and viral proteins. BMC Bioinformatics 12, 317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith, G.A., Fearnley, G.W., Abdul-Zani, I., Wheatcroft, S.B., Tomlinson, D.C., Harrison, M.A., and Ponnambalam, S. (2016). VEGFR2 trafficking, signaling and proteolysis is regulated by the ubiquitin isopeptidase USP8. Traffic 17, 53–65.

    Article  CAS  PubMed  Google Scholar 

  • Sørensen, V., Nilsen, T., and Wiedlocha, A. (2006). Functional diversity of FGF-2 isoforms by intracellular sorting. Bioessays 28, 504–514.

    Article  PubMed  CAS  Google Scholar 

  • Sorokin, A.V., Kim, E.R., and Ovchinnikov, L.P. (2007). Nucleocytoplasmic transport of proteins. Biochem Moscow 72, 1439–1457.

    Article  CAS  Google Scholar 

  • Tian, X.L., Kadaba, R., You, S.A., Liu, M., Timur, A.A., Yang, L., Chen, Q., Szafranski, P., Rao, S., Wu, L., et al. (2004). Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome. Nature 427, 640–645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valovka, T., and Hottiger, M.O. (2011). p65 controls NF-κB activity by regulating cellular localization of IκBβ. Biochem J 434, 253–263.

    Article  CAS  PubMed  Google Scholar 

  • Wiedlocha, A., and Sorensen, V. (2004). Signaling, internalization, and intracellular activity of fibroblast growth factor. Current Topics in Microbiology and Immunology 286, 45–79.

    CAS  PubMed  Google Scholar 

  • Woerner, A.C., Frottin, F., Hornburg, D., Feng, L.R., Meissner, F., Patra, M., Tatzelt, J., Mann, M., Winklhofer, K.F., Hartl, F.U., et al. (2016). Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science 351, 173–176.

    Article  CAS  PubMed  Google Scholar 

  • Yang, J., Winkler, K., Yoshida, M., and Kornbluth, S. (1999). Maintenance of G2 arrest in the Xenopus oocyte: a role for 14-3-3-mediated inhibition of Cdc25 nuclear import. EMBO J 18, 2174–2183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao, Y., Lu, Q., Hu, Z., Yu, Y., Chen, Q., and Wang, Q.K. (2017). A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure. Nat Commun 8, 133.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zabriskie, M.S., Antelope, O., Verma, A.R., Draper, L.R., Eide, C.A., Pomicter, A.D., Tran, T.H., Druker, B.J., Tyner, J.W., Miles, R.R., et al. (2018). A novel AGGF1-PDGFRb fusion in pediatric T-cell acute lymphoblastic leukemia. Haematologica 103, e87–e91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhan, M., Hori, Y., Wada, N., Ikeda, J.I., Hata, Y., Osuga, K., and Morii, E. (2016). Angiogenic factor with G-patch and FHA domain 1 (AGGF1) expression in human vascular lesions. Acta Histochem Cytochem 49, 75–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, K., Daigle, J.G., Cunningham, K.M., Coyne, A.N., Ruan, K., Grima, J.C., Bowen, K.E., Wadhwa, H., Yang, P., Rigo, F., et al. (2018a). Stress granule assembly disrupts nucleocytoplasmic transport. Cell 173, 958–971.e17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, T., He, P., and Wang, Q. (2008). AGGF1 is essential for embryonic and pathological angiogenesis. Circulation 118, S461–S462.

    Google Scholar 

  • Zhang, T., Yao, Y., Wang, J., Li, Y., He, P., Pasupuleti, V., Hu, Z., Jia, X., Song, Q., Tian, X.L., et al. (2016). Haploinsufficiency of Klippel-Trenaunay syndrome gene Aggf1 inhibits developmental and pathological angiogenesis by inactivating PI3K and AKT and disrupts vascular integrity by activating VE-cadherin. Hum Mol Genet 25, 5094–5110.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, Y., Gao, Y., Zhang, H., Zhang, J., He, F., Hnízda, A., Qian, M., Liu, X., Gocho, Y., Pui, C.H., et al. (2018b). PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute lymphoblastic leukemia. Blood 131, 2256–2261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou, B., Zeng, S., Li, N., Yu, L., Yang, G., Yang, Y., Zhang, X., Fang, M., Xia, J., and Xu, Y. (2017). Angiogenic factor with G patch and FHA domains 1 is a novel regulator of vascular injury. Arterioscler Thromb Vasc Biol 37, 675–684.

    Article  CAS  PubMed  Google Scholar 

  • Zhou, Q., Heinke, J., Vargas, A., Winnik, S., Krauss, T., Bode, C., Patterson, C., and Moser, M. (2007). ERK signaling is a central regulator for BMP-4 dependent capillary sprouting. Cardiovasc Res 76, 390–399.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (30730047, 81070262, 81130003 and 81630034). We acknowledge Mei-Qin Hu from Department of Cellular Biophysical and Neurodegenerative Disease Mechanisms (Institute of Molecular Medicine, Peking University) for his kind gifts of plasmids: pmCherry-N1 and pEGFP-C1.

Author information

Authors and Affiliations

  1. Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, 100871, China

    Cui-Fang Zhang, Han-Ming Wang, Yang Li & Xiao-Li Tian

  2. Aging and Vascular Diseases, Human Aging Research Institute and School of Life Science, Nanchang University, and Jiangxi Key Laboratory of Human Aging, Nanchang, 330031, China

    Andong Wu & Xiao-Li Tian

Authors
  1. Cui-Fang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Han-Ming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao-Li Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiao-Li Tian.

Additional information

Compliance and ethics

The author(s) declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, CF., Wang, HM., Wu, A. et al. FHA domain of AGGF1 is essential for its nucleocytoplasmic transport and angiogenesis. Sci. China Life Sci. 64, 1884–1894 (2021). https://doi.org/10.1007/s11427-020-1844-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-020-1844-0

Search

Navigation