The p21-activated kinase 3 implicated in mental retardation regulates spine morphogenesis through a Cdc42-dependent pathway
The p21-activated kinase 3 implicated in mental retardation regulates spine morphogenesis through a Cdc42-dependent pathway
复制标题
DOI：
10.1074/jbc.m703298200
复制
发表时间：
2007-07-20
影响因子：
4.8
通讯作者：
Barnier, Jean-Vianney
中科院分区：
文献类型：
--
作者：
Kreis, Patricia;Thévenot, Emmanuel;Barnier, Jean-Vianney
p21激活激酶3（PAK 3）是最近发现的基因突变导致非综合征性精神发育迟滞。PAK 3参与树突棘形态发生，是突触功能的关键调节因子。然而，PAK 3在这些过程中的潜在作用仍然知之甚少。我们在这里报告的三个突变R419 X，A365 E和R67 C，负责精神发育迟滞有不同的影响PAK 3的生物学功能。R419 X和A365 E突变完全消除激酶活性。R67 C突变显著降低PAK 3与小GTdR Cdc 42的结合，并削弱其随后被该GTdR激活。我们还报告说，PAK 3结合显着更多的Cdc 42比Rac 1和选择性激活内源性Cdc 42，表明PAK 3是Cdc 42的特异性效应。有趣的是，这三种突变蛋白在海马神经元中的表达对棘发生的影响不同。这两种激酶死亡突变体的棘的数量略有减少，但深刻改变棘的形态，而R67 C突变体的表达大幅降低棘密度。这些结果表明Cdc 42/PAK 3是树突棘形成和突触可塑性的关键模块。
The p21-activated kinase 3 (PAK3) is one of the recently identified genes for which mutations lead to nonsyndromic mental retardation. PAK3 is implicated in dendritic spine morphogenesis and is a key regulator of synaptic functions. However, the underlying roles of PAK3 in these processes remain poorly understood. We report here that the three mutations R419X, A365E, and R67C, responsible for mental retardation have different effects on the biological functions of PAK3. The R419X and A365E mutations completely abrogate the kinase activity. The R67C mutation drastically decreases the binding of PAK3 to the small GTPase Cdc42 and impairs its subsequent activation by this GTPase. We also report that PAK3 binds significantly more Cdc42 than Rac1 and is selectively activated by endogenous Cdc42, suggesting that PAK3 is a specific effector of Cdc42. Interestingly, the expression of the three mutated proteins in hippocampal neurons affects spinogenesis differentially. Both kinase-dead mutants slightly decrease the number of spines but profoundly alter spine morphology, whereas expression of the R67C mutant drastically decreases spine density. These results demonstrate that the Cdc42/PAK3 is a key module in dendritic spine formation and synaptic plasticity.