Dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) interacts with the phytanoyl-CoA α-hydroxylase associated protein I (PAHX-AP1), a brain specific protein
Dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) interacts with the phytanoyl-CoA α-hydroxylase associated protein I (PAHX-AP1), a brain specific protein
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DOI：
10.1016/j.biocel.2004.12.006
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发表时间：
2005-04-01
影响因子：
4
通讯作者：
Rahmani, Z
中科院分区：
文献类型：
--
作者：
Bescond, M;Rahmani, Z
唐氏综合征(DS)是与智力低下和发育迟缓相关的最常见的遗传缺陷。负责这些表型改变的特定基因还没有被确定。DYRK]A(双特异性酪氨酸磷酸化和调节激酶1A)是人类果蝇小脑基因(MNB)的同源基因，定位于人类21号染色体唐氏综合征关键区域，并在唐氏综合征胎儿脑中过表达。在果蝇中，小脑参与了胚胎后神经发生。在人类中，DYRK1A编码一种丝氨酸-苏氨酸激酶，尽管它可能参与唐氏综合征相关的神经生物学改变，但其生理功能尚未确定。为了深入了解它的生物学功能，我们使用酵母双杂交的方法来鉴定DYRKIA的结合伙伴。我们发现DYRKIA的C-末端区域与大脑特异的蛋白质--植酰辅酶Aα-羟基酶相关蛋白1(PAHX-AP1，又称PHYHIP)相互作用，该蛋白以前被证明与Refsum病基因产物植酰辅酶Aα-羟基酶(PAHX，又称PHYH)相互作用。共转染DYRK1a和PAHX-AP1的PC12细胞的免疫共沉淀证实了这种相互作用。此外，免疫荧光分析表明，与PAHX-AP1共定位的DYRKIA从胞核重新分布到胞浆。最后，在两种载体共转染的PC 12细胞中，DYRKIA不再能与核转录因子CREB相互作用，从而证实了在PAHX-AP1的存在下，Dyrk I A的细胞内定位从核转移到了细胞质。因此，这些数据表明，通过诱导DYRK1A重新定位到细胞质，PAHX-AP1可能参与了DYRK1A的新的细胞功能，并提示PAHX-AP1可能参与了唐氏综合征患者神经功能异常的发生。(C)2004爱思唯尔有限公司。保留所有权利。
Down syndrome (DS) is the most common genetic defect correlated with mental retardation and delayed development. The specific genes responsible for these phenotypic alterations have not yet been defined. Dyrk]A (dual-specificity tyrosine-phosphorylated and regulated kinase 1A), the human ortholog of the Drosophila minibrain gene (mnb), maps to the Down syndrome critical region of human chromosome 21 and is overexpressed in Down syndrome fetal brain. In Drosophila, minibrain is involved in postembryonic neurogenesis. In human, DYRK1A encodes a serine-threonine kinase but despite its potential involvement in the neurobiological alterations associated with Down syndrome, its physiological function has not yet been defined. To gain some insight into its biological function, we used the yeast two-hybrid approach to identify binding partners of DYRKIA. We found that the C-terminal region of DYRKIA interacts with a brain specific protein, phytanoyl-CoA alpha-hydroxylase-associated protein 1 (PAHX-AP1, also named PHYHIP) which was previously shown to interact with phytanoyl-CoA a.-hydroxylase (PAHX, also named PHYH), a Refsum disease gene product. This interaction was confirmed by co-immunoprecipitation of PC12 cells co-transfected with DYRK1A and PAHX-AP1. Furthermore, immunofluorescence analysis of PC 12 cells co-transfected with both plasmids showed a re-distribution of DYRKIA from the nucleus to the cytoplasm where it co-localized with PAHX-AP1. Finally, in PC 12 cells co-transfected with both plasmids, DYRKIA was no longer able to interact with the nuclear transcription factor CREB, thereby confirming that the intracellular localization of DYRK I A was changed from the nucleus to the cytoplasm in the presence of PAHX-AP1. Therefore, these data indicate that by inducing a re-localization of DYRK1A into the cytoplasm, PAHX-AP1 may contribute to new cellular functions of DYRK1A and suggest that PAHX-AP1 may be involved in the development of neurological abnormalities observed in Down syndrome patients. (C) 2004 Elsevier Ltd. All rights reserved.