Kidins220/ARMS Modulates the Activity of Microtubule-regulating Proteins and Controls Neuronal Polarity and Development
Kidins220/ARMS Modulates the Activity of Microtubule-regulating Proteins and Controls Neuronal Polarity and Development
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DOI：
10.1074/jbc.m109.024703
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发表时间：
2010-01-08
影响因子：
4.8
通讯作者：
Iglesias, Teresa
中科院分区：
文献类型：
--
作者：
Higuero, Alonso M.;Sanchez-Ruiloba, Lucia;Iglesias, Teresa
为了使神经元执行其功能，它们必须建立高度极化的形态，其特征在于，在大多数情况下，由单个轴突和多个树突。在此，我们发现，进化上保守的蛋白Kidins 220（220 kDa的激酶D相互作用底物），也被称为ARMS（锚蛋白重复丰富的跨膜），蛋白激酶D和神经营养因子和ephrin受体的下游效应器，调节神经元极性的建立和树突的发育。Kidins 220/ARMS功能获得和丧失实验在培养的海马神经元延伸的过程中呈现严重的表型变化。虽然Kidins 220/ARMS早期过表达阻碍神经元发育，但其通过RNA干扰的下调导致出现多个较长的轴突样延伸以及异常的树突状乔木。我们还发现Kidins 220/ARMS与微管蛋白和微管调节分子相互作用，微管调节分子在神经元形态发生中的作用已得到充分证实（微管相关蛋白1b、1a和2以及stathmin家族的两个成员）。重要的是，Kidins 220/ARMS被敲低的神经元记录了MAP 1b和stathmins磷酸化活性的变化。总之，我们的研究结果表明，Kidins 220/ARMS是一个关键的微管调节蛋白的活性调节剂，已知积极调节神经元形态发生，并提出了一种机制，它有助于控制神经元的发育。
In order for neurons to perform their function, they must establish a highly polarized morphology characterized, in most of the cases, by a single axon and multiple dendrites. Herein we find that the evolutionarily conserved protein Kidins220 (kinase D-interacting substrate of 220-kDa), also known as ARMS (ankyrin repeat-rich membrane spanning), a downstream effector of protein kinase D and neurotrophin and ephrin receptors, regulates the establishment of neuronal polarity and development of dendrites. Kidins220/ARMS gain and loss of function experiments render severe phenotypic changes in the processes extended by hippocampal neurons in culture. Although Kidins220/ARMS early overexpression hinders neuronal development, its down-regulation by RNA interference results in the appearance of multiple longer axon-like extensions as well as aberrant dendritic arbors. Wealso find that Kidins220/ARMS interacts with tubulin and microtubule-regulating molecules whose role in neuronal morphogenesis is well established (microtubule-associated proteins 1b, 1a, and 2 and two members of the stathmin family). Importantly, neurons where Kidins220/ARMS has been knocked down register changes in the phosphorylation activity of MAP1b and stathmins. Altogether, our results indicate that Kidins220/ARMS is a key modulator of the activity of microtubule-regulating proteins known to actively regulate neuronal morphogenesis and suggest a mechanism by which it contributes to control neuronal development.