Binding of laminin-1 to monosialoganglioside GM1 in lipid rafts is crucial for neurite outgrowth.
Laminin-1, an extracellular matrix molecule, promotes neurite outgrowth through the interaction of integrin and actin. Monosialoganglioside GM1 in the lipid rafts associates with and activates the NGF receptor TrkA, and enhances neurite outgrowth. However, the role of GM1 in laminin-1-induced neurite outgrowth was still unclear. Here, we describe that laminin-1 binds to GM1 through a carbohydrate moiety and a specific conformation of GM1, induces focal formation of large clusters of GM1, and enhances the relocation of TrkA in the membrane of dorsal root ganglion (DRG) and PC12 cells. We found that laminin-1-mediated clustering of GM1 causes the translocation and enrichment of beta1 integrin in lipid rafts--where TrkA colocalizes with beta1 integrin--and the activation of Lyn, Akt and MAPK to promote the outgrowth of neurites. Our results suggest that the binding of laminin-1 to GM1 facilitates the formation of a focal microdomain in the membrane, and enhances signal transduction that promotes neurite outgrowth by linking NGF-TrkA signaling with the laminin-integrin signaling pathways.
Ichikawa
Naoki
N
Research Institute for Diseases of Old Age, Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
Iwabuchi
Kazuhisa
K
Kurihara
Hidetake
H
Ishii
Kumiko
K
Kobayashi
Toshihide
T
Sasaki
Takako
T
Hattori
Nobutaka
N
Mizuno
Yoshikuni
Y
Hozumi
Kentaro
K
Yamada
Yoshihiko
Y
Arikawa-Hirasawa
Eri
E
D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005677:G(M1) Ganglioside / Q000031:analogs & derivatives / Q000378:metabolism*; D019012:Integrin beta1 / Q000187:drug effects / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism* / Q000494:pharmacology; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D016253:Microscopy, Immunoelectron; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D020917:Receptor, trkA / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D004791:Enzyme Inhibitors; D019012:Integrin beta1; D007797:Laminin; D011720:Pyrazoles; D011743:Pyrimidines; C121346:laminin 1; D005677:G(M1) Ganglioside; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D019061:src-Family Kinases