Neurochemical Research

, Volume 35, Issue 5, pp 789–796 | Cite as

Leucine-Rich Glioma Inactivated 3 Induces Neurite Outgrowth Through Akt and Focal Adhesion Kinase

  • Woo-Jae Park
  • Yun Young Lim
  • Nyoun Soo Kwon
  • Kwang Jin Baek
  • Dong-Seok Kim
  • Hye-Young Yun
Original Paper


Leucine-rich glioma inactivated 3 (LGI3) is a secreted protein that belongs to LGI/epitempin family. LGI3 is highly expressed in brain in a transcriptionally and developmentally regulated manner. Here we found that LGI3 induced neurite outgrowth in Neuro-2a cells and dorsal root ganglia explants. LGI3 treatment or overexpression increased neurite outgrowth and knockdown of LGI3 by siRNA had opposite effect. LGI3 treatment increased phosphorylation of Akt and a 125-kDa protein. Immunoprecipitation identified the 125-kDa protein as focal adhesion kinase (FAK). LGI3 overexpression increased phospho-Akt, phospho-FAK and FAK protein. Inhibition of Akt activation by PI3 kinase inhibitor attenuated LGI3-induced FAK phosphorylation and neurite outgrowth. Taken together, we propose that LGI3 is a neuritogenic factor whose signaling pathway involves Akt-mediated FAK activation.


LGI3 Neurite Akt FAK Phosphorylation Differentiation 



We thank Dr. J. L. Noebels (Baylor College of Medicine) for providing pcDNA3.1-LGI3-myc. This research was supported by the Chung-Ang University Research Grants in 2010.


  1. 1.
    Gu W, Wevers A, Schroder H, Grzeschik KH, Derst C, Brodtkorb E, de Vos R, Steinlein OK (2002) The LGI1 gene involved in lateral temporal lobe epilepsy belongs to a new subfamily of leucine-rich repeat proteins. FEBS Lett 519:71–76CrossRefPubMedGoogle Scholar
  2. 2.
    Lee SE, Lee AY, Park WJ, Jun DH, Kwon NS, Baek KJ, Kim YG, Yun HY (2006) Mouse LGI3 gene: expression in brain and promoter analysis. Gene 372:8–17CrossRefPubMedGoogle Scholar
  3. 3.
    Kobe B, Kajava AV (2001) The leucine-rich repeat as a protein recognition motif. Curr Opin Struct Biol 11:725–732CrossRefPubMedGoogle Scholar
  4. 4.
    Staub E, Perez-Tur J, Siebert R, Nobile C, Moschonas NK, Deloukas P, Hinzmann B (2002) The novel EPTP repeat defines a superfamily of proteins implicated in epileptic disorders. Trends Biochem Sci 27:441–444CrossRefPubMedGoogle Scholar
  5. 5.
    Scheel H, Tomiuk S, Hofmann K (2002) A common protein interaction domain links two recently identified epilepsy genes. Hum Mol Genet 11:1757–1762CrossRefPubMedGoogle Scholar
  6. 6.
    Chernova OB, Somerville RP, Cowell JK (1998) A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors. Oncogene 17:2873–2881CrossRefPubMedGoogle Scholar
  7. 7.
    Krex D, Hauses M, Appelt H, Mohr B, Ehninger G, Schackert HK, Schackert G (2002) Physical and functional characterization of the human LGI1 gene and its possible role in glioma development. Acta Neuropathol (Berl) 103:255–266CrossRefGoogle Scholar
  8. 8.
    Kalachikov S, Evgrafov O, Ross B, Winawer M, Barker-Cummings C, Martinelli BF, Choi C, Morozov P, Das K, Teplitskaya E, Yu A, Cayanis E, Penchaszadeh G, Kottmann AH, Pedley TA, Hauser WA, Ottman R, Gilliam TC (2002) Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet 30:335–341CrossRefPubMedGoogle Scholar
  9. 9.
    Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sirerol S, Saenz A, Poza JJ, Galan J, Gesk S, Sarafidou T, Mautner VF, Binelli S, Staub E, Hinzmann B, French L, Prud’homme JF, Passarelli D, Scannapieco P, Tassinari CA, Avanzini G, Marti-Masso JF, Kluwe L, Deloukas P, Moschonas NK, Michelucci R, Siebert R, Nobile C, Perez-Tur J, Lopez DM (2002) Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum Mol Genet 11:1119–1128CrossRefPubMedGoogle Scholar
  10. 10.
    Gu W, Brodtkorb E, Steinlein OK (2002) LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures. Ann Neurol 52:364–367CrossRefPubMedGoogle Scholar
  11. 11.
    Bermingham JR Jr, Shearin H, Pennington J, O’Moore J, Jaegle M, Driegen S, van Zon A, Darbas A, Ozkaynak E, Ryu EJ, Milbrandt J, Meijer D (2006) The claw paw mutation reveals a role for Lgi4 in peripheral nerve development. Nat Neurosci 9:76–84CrossRefPubMedGoogle Scholar
  12. 12.
    Sirerol-Piquer MS, Ayerdi-Izquierdo A, Morante-Redolat JM, Herranz-Perez V, Favell K, Barker PA, Perez-Tur J (2006) The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface. Hum Mol Genet 15:3436–3445CrossRefPubMedGoogle Scholar
  13. 13.
    Senechal KR, Thaller C, Noebels JL (2005) ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy. Hum Mol Genet 14:1613–1620CrossRefPubMedGoogle Scholar
  14. 14.
    Kimura N, Ishii Y, Suzaki S, Negishi T, Kyuwa S, Yoshikawa Y (2007) Aβ upregulates and colocalizes with LGI3 in cultured rat astrocytes. Cell Mol Neurobiol 27:335–350CrossRefPubMedGoogle Scholar
  15. 15.
    Okabayashi S, Kimura N (2007) Immunohistochemical and biochemical analyses of LGI3 in monkey brain: LGI3 accumulates in aged monkey brains. Cell Mol Neurobiol 27:819–830CrossRefPubMedGoogle Scholar
  16. 16.
    Okabayashi S, Kimura N (2008) Leucine-rich glioma inactivated 3 is involved in amyloid β peptide uptake by astrocytes and endocytosis itself. Neuroreport 19:1175–1179CrossRefPubMedGoogle Scholar
  17. 17.
    Park WJ, Lee SE, Kwon NS, Baek KJ, Kim DS, Yun HY (2008) Leucine-rich glioma inactivated 3 associates with syntaxin 1. Neurosci Lett 444:240–244CrossRefPubMedGoogle Scholar
  18. 18.
    Adan RAH, van der Kraan M, Doornbos RP, Bär PR, Burbach JPH, Gispen WH (1996) Melanocortin receptors mediate α-MSH-induced stimulation of neurite outgrowth in neuro 2A cells. Brain Res Mol Brain Res 36:37–44CrossRefPubMedGoogle Scholar
  19. 19.
    Sarnat HB, Nochlin D, Born DE (1998) Neuronal nuclear antigen (NeuN): a marker of neuronal maturation in early human fetal nervous system. Brain Dev 20:88–94CrossRefPubMedGoogle Scholar
  20. 20.
    Herranz-Perez V, Olucha-Bordonau FE, Morante-Redolat JM, Perez-Tur J (2010) Regional distribution of the leucine-rich glioma inactivated (LGI) gene family transcripts in the adult mouse brain. Brain Res 1307:177–194CrossRefPubMedGoogle Scholar
  21. 21.
    Tucker BA, Rahimtula M, Mearow KM (2008) Src and FAK are key early signalling intermediates required for neurite growth in NGF-responsive adult DRG neurons. Cell Signal 20:241–257CrossRefPubMedGoogle Scholar
  22. 22.
    Ivankovic-Dikic I, Gronroos E, Blaukat A, Barth BU, Dikic I (2000) Pyk2 and FAK regulate neurite outgrowth induced by growth factors and integrins. Nat Cell Biol 2:574–581CrossRefPubMedGoogle Scholar
  23. 23.
    Cavallaro U, Christofori G (2004) Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 4:118–132PubMedGoogle Scholar
  24. 24.
    Read DE, Gorman AM (2009) Involvement of Akt in neurite outgrowth. Cell Mol Life Sci 66:2975–2984CrossRefPubMedGoogle Scholar
  25. 25.
    Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Woo-Jae Park
    • 1
  • Yun Young Lim
    • 2
  • Nyoun Soo Kwon
    • 1
  • Kwang Jin Baek
    • 1
  • Dong-Seok Kim
    • 1
  • Hye-Young Yun
    • 1
  1. 1.Department of BiochemistryChung-Ang University College of MedicineSeoulRepublic of Korea
  2. 2.Department of DermatologyChung-Ang University College of MedicineSeoulRepublic of Korea

Personalised recommendations