MINK and TNIK differentially act on Rap2-mediated signal transduction to regulate neuronal structure and AMPA receptor function.
MINK and TNIK differentially act on Rap2-mediated signal transduction to regulate neuronal structure and AMPA receptor function.
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DOI：
10.1523/jneurosci.4124-10.2010
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发表时间：
2010-11-03
期刊：
影响因子：
--
通讯作者：
Sheng M
中科院分区：
文献类型：
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作者：
Hussain NK;Hsin H;Huganir RL;Sheng M
畸形/ nks相关激酶（MINK）和密切相关的TRAF2/ nks相互作用激酶（TNIK）是特异性结合活化Rap2的蛋白质，因此被假设为传递其下游信号转导。活化的Rap2已被发现刺激树突修剪，降低突触密度并导致突触AMPA受体（AMPA- rs）的移除。在这里，我们报道了MINK和TNIK是突触后富集的蛋白，它们在树突内的聚集受到Rap2激活状态的双向调节。神经元中MINK和TNIK的表达是正常树突形成和AMPA受体表面表达所必需的。不能与Rap2相互作用的MINK突变体过表达导致树突分支减少，这种由MINK介导的对神经元形态的影响依赖于Rap2的激活。虽然类似截断的TNIK也降低了神经元的复杂性，但其效果不需要Rap2的活性。此外，rap2介导的脊髓表面AMPA-Rs的去除完全被MINK而不是TNIK的共表达所消除。因此，尽管MINK和TNIK都结合gtp结合的Rap2，但这些激酶采用不同的机制来调节Rap2介导的信号传导。MINK似乎通过结合活化的Rap2来拮抗Rap2信号转导。我们认为MINK与Rap2的相互作用在维持树突形态完整性和突触传递中起着关键作用。
Misshapen/NIKs-related Kinase (MINK) and closely related TRAF2/Nck-interacting kinase (TNIK) are proteins that specifically bind to activated Rap2 and are thus hypothesized to relay its downstream signal transduction. Activated Rap2 has been found to stimulate dendritic pruning, reduce synaptic density and cause removal of synaptic AMPA receptors (AMPA-Rs). Here we report that MINK and TNIK are postsynaptically enriched proteins whose clustering within dendrites is bi-directionally regulated by the activation state of Rap2. Expression of MINK and TNIK in neurons is required for normal dendritic arborization and surface expression of AMPA receptors. Overexpression of a truncated MINK mutant unable to interact with Rap2 leads to reduced dendritic branching and this MINK-mediated effect on neuronal morphology is dependent upon Rap2 activation. While similarly truncated TNIK also reduces neuronal complexity, its effect does not require Rap2 activity. Furthermore, Rap2-mediated removal of surface AMPA-Rs from spines is entirely abrogated by co-expression of MINK, but not TNIK. Thus, although both MINK and TNIK bind GTP-bound Rap2, these kinases employ distinct mechanisms to modulate Rap2-mediated signaling. MINK appears to antagonize Rap2 signal transduction by binding to activated Rap2. We suggest that MINK interaction with Rap2 plays a critical role in maintaining the morphological integrity of dendrites and synaptic transmission.