PMID:24090963

Citation	Zhou, C, Li, C, Li, D, Wang, Y, Shao, W, You, Y, Peng, J, Zhang, X, Lu, L and Shen, X (2013) BIG1, a brefeldin A-inhibited guanine nucleotide-exchange protein regulates neurite development via PI3K-AKT and ERK signaling pathways. Neuroscience 254C:361-368
Abstract	The elongation of neuron is highly dependent on membrane trafficking. Brefeldin A (BFA)-inhibited guanine nucleotide-exchange protein 1 (BIG1) functions in the membrane trafficking between the Golgi apparatus and the plasma membrane. BFA, an uncompetitive inhibitor of BIG1 can inhibit neurite outgrowth and polarity development. In this study, we aimed to define the possible role of BIG1 in neurite development and to further investigate the potential mechanism. By immunostaining, we found that BIG1 was extensively colocalized with synaptophysin, a marker for synaptic vesicles in soma and partly in neurites. The amount of both protein and mRNA of BIG1 were up-regulated during rat brain development. BIG1 depletion significantly decreased the neurite length and inhibited the phosphorylation of phosphatidylinositide 3-kinase (PI3K) and protein kinase B (AKT). Inhibition of BIG1 guanine nucleotide-exchange factor (GEF) activity by BFA or overexpression of the dominant-negative BIG1 reduced PI3K and AKT phosphorylation, indicating regulatory effects of BIG1 on PI3K-AKT signaling pathway is dependent on its GEF activity. BIG1 siRNA or BFA treatment also significantly reduced extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of wild-type BIG1 significantly increased ERK phosphorylation, but the dominant-negative BIG1 had no effect on ERK phosphorylation, indicating the involvement of BIG1 in ERK signaling regulation may not be dependent on its GEF activity. Our result identified a novel function of BIG1 in neurite development. The newly recognized function integrates the function of BIG1 in membrane trafficking with the activation of PI3K-AKT and ERK signaling pathways which are critical in neurite development.
Links	PubMed Online version:10.1016/j.neuroscience.2013.09.045
Keywords
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:BIG1		GO:0031175: neuron projection development	ECO:0000315:		P		As shown in Figure 3A and B, a knockdown in wild type BIG1 led to a significant reduction in the development of neurites, or neuron projections.	complete CACAO 9029
RAT:BIG1		GO:0051897: positive regulation of protein kinase B signaling cascade	ECO:0000315:		P		As shown in Figure 5C, knockdowns of BIG1 lead to significantly reduced phosphorylation of AKT in the protein kinase B signalling pathway, as compared to the wild type.	complete CACAO 9030
RAT:BIG1	involved_in	GO:0031175: neuron projection development	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
RAT:BIG1	involved_in	GO:0051897: positive regulation of protein kinase B signaling	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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