Division of Neurobiology, Department of Molecular and Cell Biology, and Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA.
Neuron. 2011 Jan 27;69(2):231-43. doi: 10.1016/j.neuron.2010.12.021.
Ubiquitin E3 ligases serve for ubiquitination of specific substrates, and its ligase efficacy is regulated by interacting proteins or substrate modifications. Whether and how the ligases themselves are modified by cellular signaling is unclear. Here we report that protein kinase A (PKA)-dependent phosphorylation of Smad Ubiquitin Regulatory Factor 1 (Smurf1) can switch its substrate preference between two proteins of opposing actions on axon development. Extracellular factors that promote axon formation elevated Smurf1 phosphorylation at a PKA site Thr³⁰⁶, and preventing this phosphorylation reduced axon formation in cultured hippocampal neurons and impaired polarization of cortical neurons in vivo. Thr³⁰⁶-phosphorylation changed the relative affinities of Smurf1 for its substrates, leading to reduced degradation of polarity protein Par6 and increased degradation of growth-inhibiting RhoA. Thus, PKA-dependent phosphorylation of the E3 ligase could switch its substrate preference, contributing to selective protein degradation required for localized cellular function.
泛素 E3 连接酶用于特定底物的泛素化，其连接酶活性受相互作用的蛋白质或底物修饰的调节。目前尚不清楚连接酶本身是否会受到细胞信号的修饰。本研究报道，蛋白激酶 A（PKA）依赖性磷酸化 Smad 泛素调节因子 1（Smurf1）可以改变其对轴突发育具有相反作用的两种蛋白质的底物偏好性。促进轴突形成的细胞外因子会增加 Smurf1 在 PKA 位点 Thr³⁰⁶的磷酸化，而阻止这种磷酸化会减少培养的海马神经元中的轴突形成，并损害体内皮质神经元的极化。Thr³⁰⁶磷酸化改变了 Smurf1 与其底物的相对亲和力，导致极性蛋白 Par6 的降解减少和生长抑制性 RhoA 的降解增加。因此，E3 连接酶的 PKA 依赖性磷酸化可以改变其底物偏好性，有助于选择性蛋白质降解，以实现局部细胞功能。
