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AKT-independent Reelin signaling requires interactions of heterotrimeric Go and Src
- Source :
- Biochemical and biophysical research communications. 467(4)
- Publication Year :
- 2015
-
Abstract
- Reelin, a large secreted extracellular matrix glycoprotein, plays a key role in neuronal migration during cortical development and promotes neuronal maturation. The signaling pathway regulating neuronal maturation in the postnatal period are relatively less well understood. In this study, we demonstrated that a heterotrimeric G protein, Go, is a novel target of Reelin-induced signaling to promote neurite outgrowth. In primary hippocampal neurons of Reelin-deficient reeler mice, neurite outgrowth was significantly reduced and rescued upon addition of Reelin. Pertussis toxin (PTX) treatment or transfection with Gαo-siRNA suppressed Reelin-mediated neurite outgrowth in wild-type neurons. Additionally, Reelin treatment led to increased phosphorylation of AKT, GSK3β, and JNK, which were all effectively blocked by the PI3K inhibitor, LY294002. By comparison, PTX specifically blocked JNK activation, but not AKT and GSK3β. Immunoprecipitation assays disclosed that Reelin increases the active forms of both Src and Gαo and promotes their direct association. Notably, Dab1, a cytoplasmic adaptor molecule that mediates Reelin signaling, did not interact with Gαo. Neurite outgrowth by Reelin was induced via activating Src kinase, which directly stimulated Gαo, activity, leading to JNK activation. Based on the collective findings, we suggest that Reelin-dependent signaling mechanisms may be split into Src-AKT-dependent and Src-Go-dependent pathways. Our results additionally provide evidence that Reelin receptors cross-communicate with heterologous G protein-coupled receptors (GPCR) independently of the cognate ligands of GPCR.
- Subjects :
- Neurite
Cell Adhesion Molecules, Neuronal
Biophysics
Nerve Tissue Proteins
Biochemistry
Mice
Reeler
Heterotrimeric G protein
Animals
Reelin
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Extracellular Matrix Proteins
biology
Serine Endopeptidases
Cell Biology
DAB1
Heterotrimeric GTP-Binding Proteins
Cell biology
Reelin Protein
src-Family Kinases
nervous system
biology.protein
Signal transduction
Proto-Oncogene Proteins c-akt
Signal Transduction
Subjects
Details
- ISSN :
- 10902104
- Volume :
- 467
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Biochemical and biophysical research communications
- Accession number :
- edsair.doi.dedup.....81ed9a24054c1f3c825084b1767f37d2