Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated Aβ toxicity in Drosophila.
Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated Aβ toxicity in Drosophila.
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DOI：
10.1038/ncomms2278
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发表时间：
2012
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
保守的蛋白激酶PAR-1/Mark在细胞不对称分裂、细胞极性和神经元分化等过程中发挥重要作用。他们的放松管制被认为与阿尔茨海默氏症和癌症等疾病有关。鉴于PAR-1/Mark在健康和疾病中的重要性，它们的活动需要严格控制。然而，对它们在体内调节的分子机制知之甚少。在这里，我们展示了在果蝇中，依赖于磷酸化的泛素化机制抑制了PAR-1的激活。由LKB1控制的磷酸化产生的活性PAR-1被SCF(Skp，Cullin，F-box Containing Complex)(SLimb)泛素化和降解为靶点，其作用被去泛素化酶脂肪面拮抗。这个新发现的PAR-1修饰模块对果蝇神经肌肉接头处阿尔茨海默病的病原体淀粉样前体蛋白(APP)/Aβ-42的突触形态和tau介导的突触后毒性具有关键调节作用。我们的结果为了解PAR-1在不同生理过程中的调控提供了新的见解，并为涉及PAR-1/MARK去调控的疾病提供了新的治疗策略。
The conserved kinases PAR-1/MARK are critically involved in processes such as asymmetric cell division, cell polarity and neuronal differentiation. Their deregulation has been implicated in diseases including Alzheimer’s disease and cancer. Given the importance of PAR-1/MARK in health and disease, their activities need to be tightly controlled. However, little is known about the molecular mechanisms underlying their regulation in vivo. Here we show that in Drosophila, a phosphorylation-dependent ubiquitination mechanism restrains PAR-1 activation. Active PAR-1 generated by LKB1-controlled phosphorylation is targeted for ubiquitination and degradation by SCF (Skp, Cullin, F-box containing complex) (Slimb), whose action is antagonized by the deubiquitinating enzyme fat facets. This newly identified PAR-1-modifying module critically regulates synaptic morphology and tau-mediated postsynaptic toxicity of amyloid precursor protein (APP)/Aβ-42, the causative agents of Alzheimer’s disease, at the Drosophila neuromuscular junction. Our results provide new insights into the regulation of PAR-1 in various physiological processes and offer new therapeutic strategies for diseases involving PAR-1/MARK deregulation.
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影响因子：
4.1
作者：
Al-Hakim, Abdallah K.;Zagorska, Anna;Alessi, Dario R.
通讯作者：
Alessi, Dario R.
影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi
影响因子：
6.1
作者：
Almeida, CG;Tampellini, D;Gouras, GK
通讯作者：
Gouras, GK
影响因子：
64.8
作者：
Ko, HW;Jiang, J;Edery, I
通讯作者：
Edery, I
影响因子：
64.8
作者：
DiAntonio, A;Haghighi, AP;Goodman, CS
通讯作者：
Goodman, CS