Implication of geranylgeranyltransferase I in synapse formation.
Agrin activates the transmembrane tyrosine kinase MuSK to mediate acetylcholine receptor (AChR) clustering at the neuromuscular junction (NMJ). However, the intracellular signaling mechanism downstream of MuSK is poorly characterized. This study provides evidence that geranylgeranyltransferase I (GGT) is an important signaling component in the Agrin/MuSK pathway. Agrin causes a rapid increase in tyrosine phosphorylation of the alpha(G/F) subunit of GGT and in GGT activity. Inhibition of GGT activity or expression prevents muscle cells from forming AChR clusters in response to Agrin and attenuates the formation of neuromuscular synapses in spinal neuron-muscle cocultures. Importantly, transgenic mice expressing an alpha(G/F) mutant demonstrate NMJ defects with wider endplate bands and smaller AChR plaques. These results support the notion that prenylation is necessary for AChR clustering and the NMJ formation and/or maintenance, revealing an active role of GGT in Agrin/MuSK signaling.
Luo
Zhen G
ZG
Department of Neurobiology, Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Je
Hyun-Soo
HS
Wang
Qiang
Q
Yang
Feng
F
Dobbins
G Clem
GC
Yang
Zhi-Hua
ZH
Xiong
Wen C
WC
Lu
Bai
B
Mei
Lin
L
D018171:Agrin / Q000378:metabolism* / Q000494:pharmacology; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development*; D009924:Organ Culture Techniques; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D017368:Protein Prenylation / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism; D013570:Synaptic Membranes / Q000201:enzymology* / Q000235:genetics; D014443:Tyrosine / Q000378:metabolism; D014982:Xenopus laevis; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D018171:Agrin; D004791:Enzyme Inhibitors; D010455:Peptides; D021122:Protein Subunits; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; D014443:Tyrosine; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C475048:MuSK protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D020741:rho GTP-Binding Proteins