PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2.
PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2.
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DOI：
10.3389/fnmol.2017.00417
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发表时间：
2017
影响因子：
4.8
通讯作者：
Greggio E
中科院分区：
文献类型：
--
作者：
Civiero L;Cogo S;Kiekens A;Morganti C;Tessari I;Lobbestael E;Baekelandt V;Taymans JM;Chartier-Harlin MC;Franchin C;Arrigoni G;Lewis PA;Piccoli G;Bubacco L;Cookson MR;Pinton P;Greggio E
富含亮氨酸重复序列激酶2（LRRK 2）的突变与帕金森病（PD）相关，因此，LRRK 2被认为是年龄相关神经退行性变的有希望的治疗靶点。虽然LRRK 2在健康和疾病中的细胞功能还不完全清楚，但有力的证据表明，PD相关突变改变了LRRK 2激酶和GT3活性，从而导致下游信号通路的失调。我们以前已经证明，一个LRRK 2结合伴侣是P21（RAC 1）激活的激酶6（PAK 6）。在这里，我们询问PAK 6相互作用组，发现PAK 6以激酶依赖性方式结合14-3-3蛋白的子集。此外，PAK 6在Ser 59处有效地磷酸化14-3-3γ，并且这种磷酸化充当开关以使伴侣蛋白从客户蛋白（包括LRRK 2，一种良好建立的14-3-3结合配偶体）解离。我们发现被PAK 6磷酸化的14-3-3γ不再能够在磷酸化Ser 935处结合LRRK 2，导致LRRK 2去磷酸化。为了解决这些相互作用是否与神经元相关，我们证明了PAK 6的组成型活性形式通过14-3-3γ的磷酸化来挽救G2019 S LRRK 2相关的神经突缩短。我们的研究结果证实PAK 6是14-3-3γ的激酶，揭示了14-3-3/LRRK 2复合物在脑内的一种新的调节机制。
Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for age-related neurodegeneration. Although the cellular functions of LRRK2 in health and disease are incompletely understood, robust evidence indicates that PD-associated mutations alter LRRK2 kinase and GTPase activities with consequent deregulation of the downstream signaling pathways. We have previously demonstrated that one LRRK2 binding partner is P21 (RAC1) Activated Kinase 6 (PAK6). Here, we interrogate the PAK6 interactome and find that PAK6 binds a subset of 14-3-3 proteins in a kinase dependent manner. Furthermore, PAK6 efficiently phosphorylates 14-3-3γ at Ser59 and this phosphorylation serves as a switch to dissociate the chaperone from client proteins including LRRK2, a well-established 14-3-3 binding partner. We found that 14-3-3γ phosphorylated by PAK6 is no longer competent to bind LRRK2 at phospho-Ser935, causing LRRK2 dephosphorylation. To address whether these interactions are relevant in a neuronal context, we demonstrate that a constitutively active form of PAK6 rescues the G2019S LRRK2-associated neurite shortening through phosphorylation of 14-3-3γ. Our results identify PAK6 as the kinase for 14-3-3γ and reveal a novel regulatory mechanism of 14-3-3/LRRK2 complex in the brain.
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影响因子：
15.1
作者：
Belluzzi E;Gonnelli A;Cirnaru MD;Marte A;Plotegher N;Russo I;Civiero L;Cogo S;Carrion MP;Franchin C;Arrigoni G;Beltramini M;Bubacco L;Onofri F;Piccoli G;Greggio E
通讯作者：
Greggio E
PAK 激酶的结构、生物化学和生物学
影响因子：
3.5
作者：
Kumar R;Sanawar R;Li X;Li F
通讯作者：
Li F
DOI：
10.1016/j.bbrc.2009.08.163
发表时间：
2009-11-20
影响因子：
3.1
作者：
Greggio, Elisa;Taymans, Jean-Marc;Zhen, Eugene Yuejun;Ryder, John;Vancraenenbroeck, Renee;Beilina, Alexandra;Sun, Peng;Deng, Junpeng;Jaffe, Howard;Baekelandt, Veerle;Merchant, Kalpana;Cookson, Mark R.
通讯作者：
Cookson, Mark R.
影响因子：
4.4
作者：
Gloeckner, Christian Johannes;Boldt, Karsten;Ueffing, Marius
通讯作者：
Ueffing, Marius
影响因子：
4.8
作者：
Greggio, Elisa;Zambrano, Ibardo;Cookson, Mark R.
通讯作者：
Cookson, Mark R.