Abstract
JLP (JNK-associated leucine zipper protein) is a novel scaffolding protein involved in JNK signaling. Although it is known that JLP is highly expressed in brain, the biological function of JLP in neuronal systems remains unknown. Here, we report a novel interaction between JLP and SCG10 (superior cervical ganglia clone 10), which is a microtubule-destabilizing factor that is essential for neurite outgrowth. Inhibition of endogenous JLP expression using small interference RNA methodology strongly enhanced nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Our results show that JLP negatively regulates NGF-induced neurite outgrowth by decreasing the level of phosphorylated SCG10. Furthermore, inhibition of JNK phosphorylation by a small molecule inhibitor, SP600125, resulted in inhibition of SCG10 phosphorylation and inhibition of neurite growth. Taken together, our results suggest that JLP negatively regulates NGF-induced neurite outgrowth through a sequestering mechanism that results in an attenuation of NGF-induced SCG10 phosphorylation.
Highlights
SCG10, a neural-specific phosphoprotein, plays a critical role in neuronal development through its microtubule-destabilizing activity [4, 5]
As predicted by our results obtained with COS-7 cells, these studies showed that immunoprecipitates of SCG10 contained detectable levels of JLP, suggesting that endogenous JLP interacted with endogenous SCG10 during nerve growth factor (NGF)-induced differentiation of PC12 cells (Fig. 2C)
To define the mechanism by which loss of JLP enhances neurite outgrowth, we examined whether JLP regulates SCG10 phosphorylation during NGF-induced differentiation
Summary
SCG10, a neural-specific phosphoprotein, plays a critical role in neuronal development through its microtubule-destabilizing activity [4, 5]. The microtubule-destabilizing activity of SCG10 is dependent on the phosphorylation status of the protein [7] and inhibition of JNK activity by small molecule inhibitors was found to abrogate the ability of SCG10 to mediate tubulin depolymerization These observations suggest that SCG10 phosphorylation is a critical step in microtubule homeostasis and axondendritic growth during brain development [8]. JNKs participate in multiprotein cascades with upstream activators and downstream effectors This kinase cascade is regulated spatiotemporally by scaffolding proteins such as the JIP/JSAP/JLP family [9, 10]. Regulation of Neurite Outgrowth by JLP and SCG10 regulates NGF-induced neurite outgrowth by inhibiting JNKdependent phosphorylation of SCG10 This is the first indication that JLP mediates neurite outgrowth through the specific interaction with microtubule dynamics regulators, suggesting a novel role for the JIP/JLP family of scaffolding protein in neuronal differentiation and development
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