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RC3/neurogranin negatively regulates extracellular signal-regulated kinase pathway through its interaction with Ras

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Abstract

RC3/neurogranin is a postsynaptic protein and plays pivotal roles in spatial learning and emotional anxiety as well as synaptic plasticity. The expression level of RC3 is dynamically changed during developmental stages, but the function of RC3 in brain development is not well understood yet. Neurotrophins interact with tropomyosin-related kinase receptors to activate Ras–extracellular signal-regulated kinase (ERK) pathway and can also induce neuronal differentiation. In this study, we demonstrate that RC3 inhibits Ras–ERK pathway by interaction with Ras and controls neurite outgrowth induced by neurotrophins. In PC12 cells, RC3 inhibits nerve growth factor (NGF)-induced activation of Ras and thereby ERK1/2 signaling cascade as well as neurite outgrowth induced by NGF. We found Ras is the target of the inhibitory function of RC3, because RC3 interacts with Ras and suppresses the elevated affinity of Ras to Ras-binding domain of Raf-1. Meanwhile, already activated Raf-1 by Ras activity is not affected by RC3. Furthermore, depletion of RC3 by RNA interference drastically enhances the stimulation of ERK1/2 and neurite outgrowth induced by brain-derived neurotrophic factor in hippocampal neurons. These findings suggest that RC3 is a novel natural inhibitor of Ras-ERK1/2 signaling axis, leading to negatively regulate neuronal differentiation induced by neurotrophins.

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Acknowledgments

We thank Drs. R. Krug (University of Wuerzburg, Germany) for Raf1 and MEK1(K97R) cDNA, and C. Herrmann (Max Plank Institute of Molecular Physiology, Germany) for GST-Raf(RBD) cDNA. This work was supported by a National Research Foundation Grant (2006-0093855) and a NRF Grant (2011-0030141) through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (MEST) of the Korea, and by a Korea University Grant (E.-J.C.).

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  1. Kwang Je Kim

    Present address: Ministry of Food and Drug Safety, Osong Health Technology Administration Complex, 187 Osongsaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, Republic of Korea

Authors and Affiliations

  1. Laboratory of Cell Death and Human Disease, Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul, 136-701, Republic of Korea

    Kanghyun Ryoo, Sang-gil Hwang, Kwang Je Kim & Eui-Ju Choi

  2. WCI Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 136-791, Republic of Korea

    Kanghyun Ryoo

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  1. Kanghyun Ryoo
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Correspondence to Eui-Ju Choi.

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Ryoo, K., Hwang, Sg., Kim, K.J. et al. RC3/neurogranin negatively regulates extracellular signal-regulated kinase pathway through its interaction with Ras. Mol Cell Biochem 402, 33–40 (2015). https://doi.org/10.1007/s11010-014-2311-0

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