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. 2009 Jul 15;315(12):2043-52.
doi: 10.1016/j.yexcr.2009.03.012. Epub 2009 Mar 25.

Valproic Acid-Inducible Arl4D and cytohesin-2/ARNO, Acting Through the Downstream Arf6, Regulate Neurite Outgrowth in N1E-115 Cells

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Valproic Acid-Inducible Arl4D and cytohesin-2/ARNO, Acting Through the Downstream Arf6, Regulate Neurite Outgrowth in N1E-115 Cells

Junji Yamauchi et al. Exp Cell Res. .

Abstract

The mood-stabilizing agent valproic acid (VPA) potently promotes neuronal differentiation. As yet, however, little is known about the underlying molecular mechanism. Here, we show that VPA upregulates cytohesin-2 and mediates neurite outgrowth in N1E-115 neuroblastoma cells. Cytohesin-2 is the guanine-nucleotide exchange factor (GEF) for small GTPases of the Arf family; it regulates many aspects of cellular functions including morphological changes. Treatment with the specific cytohesin family inhibitor SecinH3 or knockdown of cytohesin-2 with its siRNA results in blunted induction of neurite outgrowth in N1E-115 cells. The outgrowth is specifically inhibited by siRNA knockdown of Arf6, but not by that of Arf1. Furthermore, VPA upregulates Arl4D, an Arf-like small GTPase that has recently been identified as the regulator that binds to cytohesin-2. Arl4D knockdown displays an inhibitory effect on neurite outgrowth resulting from VPA, while expression of constitutively active Arl4D induces outgrowth. We also demonstrate that the addition of cell-permeable peptide, coupling the cytohesin-2-binding region of Arl4D into cells, reduces the effect of VPA. Thus, Arl4D is a previously unknown regulator of neurite formation through cytohesin-2 and Arf6, providing another example that the functional interaction of two different small GTPases controls an important cellular function.

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