Phosphoinositides are essential coactivators for p21-activated kinase 1.
Phosphoinositides are essential coactivators for p21-activated kinase 1.
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DOI：
10.1016/j.molcel.2010.10.015
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发表时间：
2010-11-12
期刊：
影响因子：
16
通讯作者：
Peterson JR
中科院分区：
文献类型：
--
作者：
Strochlic TI;Viaud J;Rennefahrt UE;Anastassiadis T;Peterson JR
富含磷脂的膜如质膜可作为激酶信号传导的直接调节剂。Pak 1参与质膜上的生长因子信号传导，其失调与癌症有关。Pak 1采用自抑制的构象，在与膜结合的Rho GTPases Rac 1或Cdc 42结合时被解除，但脂质是否也在体内调节Pak 1尚不清楚。我们在这里表明，磷酸肌醇，特别是PIP 2，增强Rho-GTdR介导的Pak 1活性。Pak 1的带正电荷的区域结合到含有磷酸肌醇的膜，并且这种相互作用对于Pak 1响应于细胞外信号的膜募集和激活是必不可少的。我们的研究结果强调了积极的作用，脂质的变构调节Pak 1，并建议Pak 1是一个“符合检测器”，其激活依赖于GTP酶存在于富含磷酸肌醇的膜。这些发现扩展了磷酸肌醇在激酶信号传导中的作用，并表明改变磷酸肌醇代谢可能会上调癌细胞中的Pak 1活性。
Phospholipid-enriched membranes such as the plasma membrane can serve as direct regulators of kinase signaling. Pak1 is involved in growth factor signaling at the plasma membrane and its dysregulation is implicated in cancer. Pak1 adopts an autoinhibited conformation that is relieved upon binding to membrane-bound Rho GTPases Rac1 or Cdc42, but whether lipids also regulate Pak1 in vivo is unknown. We show here that phosphoinositides, particularly PIP2, potentiate Rho-GTPase-mediated Pak1 activity. A positively charged region of Pak1 binds to phosphoinositide-containing membranes, and this interaction is essential for membrane recruitment and activation of Pak1 in response to extracellular signals. Our results highlight an active role for lipids as allosteric regulators of Pak1 and suggest that Pak1 is a “coincidence detector” whose activation depends on GTPases present in phosphoinositide-rich membranes. These findings expand the role of phosphoinositides in kinase signaling and suggest how altered phosphoinositide metabolism may upregulate Pak1 activity in cancer cells.
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