EphrinA/EphA-induced ectodomain shedding of neural cell adhesion molecule regulates growth cone repulsion through ADAM10 metalloprotease.
EphrinA/EphA-induced ectodomain shedding of neural cell adhesion molecule regulates growth cone repulsion through ADAM10 metalloprotease.
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DOI：
10.1111/jnc.12468
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发表时间：
2014-01
影响因子：
4.7
通讯作者：
Maness PF
中科院分区：
文献类型：
--
作者：
Brennaman LH;Moss ML;Maness PF
EphrinA/EphA 依赖性轴突排斥对于发育中神经元的突触靶向至关重要，但下游分子机制仍不清楚。此处，显示 ephrinA5/EphA3 触发金属蛋白酶解整合素和金属蛋白酶 (ADAM)10 对神经细胞粘附分子 (NCAM) 的蛋白水解，从而促进小鼠新皮质神经元的生长锥塌陷。 EphrinA5 诱导 ADAM10 活性，促进皮质神经元培养物中聚唾液酸-NCAM 的胞外域脱落，释放出约 250 kDa 的可溶性片段，该片段由其大部分细胞外区域组成。 NCAM 脱落依赖于 ADAM10 和 EphA3 激酶活性，如用显性失活 ADAM10 和激酶失活 EphA3 (K653R) 突变体转染的 HEK293T 细胞所示。纯化的 ADAM10 在通过质谱鉴定的第二个纤连蛋白 III 型结构域 (Leu671-Lys672/Ser673-Leu674) 的 E-F 环内的序列处切割 NCAM。 ADAM10 裂解序列内的 NCAM 突变阻止了 EphA3 诱导的 HEK293T 细胞中 NCAM 的脱落。 EphrinA5 诱导的生长锥塌陷依赖于 ADAM10 活性，在 NCAM 缺失小鼠的皮层培养物中受到抑制，并被 WT 拯救，但 NCAM 的 ADAM10 切割位点突变体则不能拯救。通过 ephrin5/EphA3/ADAM10 机制调节 NCAM 的蛋白水解可能会影响突触发育，并且在受到干扰时可能导致 NCAM 过度脱落，这与精神分裂症等神经发育障碍有关。
EphrinA/EphA-dependent axon repulsion is crucial for synaptic targeting in developing neurons but downstream molecular mechanisms remain obscure. Here, it is shown that ephrinA5/EphA3 triggers proteolysis of the neural cell adhesion molecule (NCAM) by the metalloprotease a disintegrin and metalloprotease (ADAM)10 to promote growth cone collapse in neurons from mouse neocortex. EphrinA5 induced ADAM10 activity to promote ectodomain shedding of polysialic acid-NCAM in cortical neuron cultures, releasing a ~ 250 kDa soluble fragment consisting of most of its extracellular region. NCAM shedding was dependent on ADAM10 and EphA3 kinase activity as shown in HEK293T cells transfected with dominant negative ADAM10 and kinase-inactive EphA3 (K653R) mutants. Purified ADAM10 cleaved NCAM at a sequence within the E-F loop of the second fibronectin type III domain (Leu671-Lys672/Ser673-Leu674) identified by mass spectrometry. Mutations of NCAM within the ADAM10 cleavage sequence prevented EphA3-induced shedding of NCAM in HEK293T cells. EphrinA5-induced growth cone collapse was dependent on ADAM10 activity, was inhibited in cortical cultures from NCAM null mice, and was rescued by WT but not ADAM10 cleavage site mutants of NCAM. Regulated proteolysis of NCAM through the ephrin5/EphA3/ADAM10 mechanism likely impacts synapse development, and may lead to excess NCAM shedding when disrupted, as implicated in neurodevelopmental disorders such as schizophrenia.
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影响因子：
5.6
作者：
Carafoli, Federico;Saffell, Jane L.;Hohenester, Erhard
通讯作者：
Hohenester, Erhard
影响因子：
11.3
作者：
Gray, Laura J.;Dean, Brian;Scarr, Elizabeth
通讯作者：
Scarr, Elizabeth
DOI：
10.1007/978-3-7091-0932-8_5
发表时间：
2012-01-01
期刊：
SYNAPTIC PLASTICITY: DYNAMICS, DEVELOPMENT AND DISEASE
影响因子：
--
作者：
Bukalo, Olena;Dityatev, Alexander
通讯作者：
Dityatev, Alexander
影响因子：
3.7
作者：
Brennaman, Leann H.;Zhang, Xuying;Maness, Patricia F.
通讯作者：
Maness, Patricia F.
影响因子：
6.1
作者：
Brennaman, Leann H.;Kochlamazashvili, Gaga;Stoenica, Luminita;Nonneman, Randall J.;Moy, Sheryl S.;Schachner, Melitta;Dityatev, Alexander;Maness, Patricia F.
通讯作者：
Maness, Patricia F.