BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Na/K-ATPase beta1-subunit associates with neuronal growth regulator 1 (NEGR1) to participate in intercellular interactions

  • Cheon, Yeongmi (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Yoo, Ara (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Seo, Hyunseok (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Yun, Seo-Young (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Lee, Hyeonhee (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Lim, Heeji (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Kim, Youngho (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Che, Lihua (Department of Microbiology and Molecular Biology, Chungnam National University) ;
  • Lee, Soojin (Department of Microbiology and Molecular Biology, Chungnam National University)
  • Received : 2020.05.28
  • Accepted : 2020.09.09
  • Published : 2021.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

Neuronal growth regulator 1 (NEGR1) is a GPI-anchored membrane protein that is involved in neural cell adhesion and communication. Multiple genome wide association studies have found that NEGR1 is a generic risk factor for multiple human diseases, including obesity, autism, and depression. Recently, we reported that Negr1-/- mice showed a highly increased fat mass and affective behavior. In the present study, we identified Na/K-ATPase, beta1-subunit (ATP1B1) as an NEGR1 binding partner by yeast two-hybrid screening. NEGR1 and ATP1B1 were found to form a relatively stable complex in cells, at least partially co-localizing in membrane lipid rafts. We found that NEGR1 binds with ATP1B1 at its C-terminus, away from the binding site for the alpha subunit, and may contribute to intercellular interactions. Collectively, we report ATP1B1 as a novel NEGR1-interacting protein, which may help deciphering molecular networks underlying NEGR1-associated human diseases.

Keywords

References

  1. Tokhtaeva E, Clifford RJ, Kaplan JH, Sachs G and Vagin O (2012) Subunit isoform selectivity in assembly of Na,K-ATPase alpha-beta heterodimers. J Biol Chem 287, 26115-26125 https://doi.org/10.1074/jbc.M112.370734
  2. Li C, Capendeguy O, Geering K and Horisberger JD (2005) A third Na+-binding site in the sodium pump. Proc Natl Acad Sci U S A 102, 12706-12711 https://doi.org/10.1073/pnas.0505980102
  3. Clausen MV, Hilbers F and Poulsen H (2017) The Structure and function of the Na,K-ATPase isoforms in health and disease. Front Physiol 8, 371 https://doi.org/10.3389/fphys.2017.00371
  4. Antonicek H, Persohn E and Schachner M (1987) Biochemical and functional characterization of a novel neuron-glia adhesion molecule that is involved in neuronal migration. J Cell Biol 104, 1587-1595 https://doi.org/10.1083/jcb.104.6.1587
  5. Rajasekaran SA, Huynh TP, Wolle DG et al (2010) Na,K-ATPase subunits as markers for epithelial-mesenchymal transition in cancer and fibrosis. Mol Cancer Ther 9, 1515-1524 https://doi.org/10.1158/1535-7163.MCT-09-0832
  6. Funatsu N, Miyata S, Kumanogoh H et al (1999) Characterization of a novel rat brain glycosylphosphatidylinositol-anchored protein (Kilon), a member of the IgLON cell adhesion molecule family. J Biol Chem 274, 8224-8230 https://doi.org/10.1074/jbc.274.12.8224
  7. Hashimoto T, Maekawa S and Miyata S (2009) IgLON cell adhesion molecules regulate synaptogenesis in hippocampal neurons. Cell Biochem Funct 27, 496-498 https://doi.org/10.1002/cbf.1600
  8. Kim H, Hwang JS, Lee B, Hong J and Lee S (2014) Newly identified cancer-associated role of human neuronal growth regulator 1 (NEGR1). J Cancer 5, 598-608 https://doi.org/10.7150/jca.8052
  9. Ni H, Xu M, Zhan GL et al (2018) The GWAS risk genes for depression may be actively involved in Alzheimer's disease. J Alzheimers Dis 64, 1149-1161 https://doi.org/10.3233/JAD-180276
  10. Willer CJ, Speliotes EK, Loos RJ et al (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41, 25-34 https://doi.org/10.1038/ng.287
  11. Chun Y, Park B, Koh W et al (2011) New centromeric component CENP-W is an RNA-associated nuclear matrix protein that interacts with nucleophosmin/B23 protein. J Biol Chem 286, 42758-42769 https://doi.org/10.1074/jbc.M111.228411
  12. Kim H, Chun Y, Che L, Kim J, Lee S and Lee S (2017) The new obesity-associated protein, neuronal growth regulator 1 (NEGR1), is implicated in Niemann-Pick disease Type C (NPC2)-mediated cholesterol trafficking. Biochem Biophys Res Commun 482, 1367-1374 https://doi.org/10.1016/j.bbrc.2016.12.043
  13. Kalinowska M, Castillo C and Francesconi A (2015) Quantitative profiling of brain lipid raft proteome in a mouse model of fragile X syndrome. PLoS One 10, e0121464 https://doi.org/10.1371/journal.pone.0121464
  14. Liu G, Jiang Y, Wang P et al (2012) Cell adhesion molecules contribute to Alzheimer's disease: multiple pathway analyses of two genome-wide association studies. J Neurochem 120, 190-198 https://doi.org/10.1111/j.1471-4159.2011.07547.x
  15. Rek A, Krenn E and Kungl AJ (2009) Therapeutically targeting protein-glycan interactions. Br J Pharmacol 157, 686-694 https://doi.org/10.1111/j.1476-5381.2009.00226.x
  16. Jayaprakash NG and Surolia A (2017) Role of glycosylation in nucleating protein folding and stability. Biochem J 474, 2333-2347 https://doi.org/10.1042/BCJ20170111
  17. CRG, Shoshani L and Larre I (2012) The Na+-K+-ATPase as self-adhesion molecule and hormone receptor. Am J Physiol Cell Physiol 302, C473-481 https://doi.org/10.1152/ajpcell.00083.2011
  18. Paez O, Martinez-Archundia M, Villegas-Sepulveda N, Roldan ML, Correa-Basurto J and Shoshani L (2019) A model for the homotypic interaction between Na(+), K(+)-ATPase beta1 subunits reveals the role of extracellular residues 221-229 in Its Ig-like domain. Int J Mol Sci 20, 4538 https://doi.org/10.3390/ijms20184538
  19. Lee SJ, Litan A, Li Z et al (2015) Na,K-ATPase beta1-subunit is a target of sonic hedgehog signaling and enhances medulloblastoma tumorigenicity. Mol Cancer 14, 159 https://doi.org/10.1186/s12943-015-0430-1
  20. Geering K (2008) Functional roles of Na,K-ATPase subunits. Curr Opin Nephrol Hypertens 17, 526-532 https://doi.org/10.1097/MNH.0b013e3283036cbf
  21. de Lores Arnaiz GR and Ordieres MG (2014) Brain Na(+), K(+)-ATPase activity in aging and disease. Int J Biomed Sci 10, 85-102
  22. Srikanthan K, Shapiro JI and Sodhi K (2016) The role of Na/K-ATPase signaling in oxidative stress related to obesity and cardiovascular disease. Molecules 21, 1172 https://doi.org/10.3390/molecules21091172
  23. Noh K, Lee H, Choi TY et al (2019) Negr1 controls adult hippocampal neurogenesis and affective behaviors. Mol Psychiatry 24, 1189-1205 https://doi.org/10.1038/s41380-018-0347-3
  24. Cheon Y and Lee S (2018) CENP-W inhibits CDC25A degradation by destabilizing the SCF(beta-TrCP-1) complex at G2/M. FASEB J 32, 6051-6065 https://doi.org/10.1096/fj.201701358RRR