Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity
Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity
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DOI：
10.1091/mbc.02-03-0046
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发表时间：
2002-11-01
影响因子：
3.3
通讯作者：
Mandelkow, EM
中科院分区：
文献类型：
--
作者：
Biernat, J;Wu, YZ;Mandelkow, EM
微管亲和力调节激酶(MARK)家族的蛋白激酶最初被发现是因为它们能够磷酸化tau蛋白中的某些位点(重复结构域中的KXGS基序)。这种类型的磷酸化在阿尔茨海默病脑组织中异常的tau中增强，并导致tau从微管中分离。标记相关蛋白(PAR-1和KIN1)存在于多种生物体中，参与细胞极性的建立和维持。在此，我们报道了Mark2影响神经母细胞瘤和其他细胞模型细胞突起分化和生长的能力。Mark2在KXGS基序上磷酸化tau蛋白；这导致tau从微管中分离，并使其不稳定。如果Mark2被抑制，N2a细胞中神经突起的形成就会被阻止，无论是通过转染显性负向突变体，还是通过Mark2抑制剂，如膜促性腺激素。或者，如果tau上的靶KXGS基序通过点突变而变得不可磷酸化，则神经突起被阻断。结果表明，Mark2参与了神经元极性所需的微管的可塑性和神经突起的生长。
Protein kinases Of the microtubule affinity-regulating kinase (MARK) family were originally discovered because of their ability to phosphorylate certain sites in tau protein (KXGS motifs in the repeat domain). This type of phosphorylation is enhanced in abnormal tau from Alzheimer brain tissue and causes the detachment of tau from microtubules. MARK-related kinases (PAR-1 and KIN1) occur in various organisms and are involved in establishing and maintaining cell polarity. Herein, we report the ability of MARK2 to affect the differentiation and outgrowth of cell processes from neuroblastoma and other cell models. MARK2 phosphorylates tau protein at the KXGS motifs; this results in the detachment of tau from microtubules and their destabilization. The formation of neurites in N2a cells is blocked if MARK2 is inactivated, either by transfecting a dominant negative mutant, or by MARK2 inhibitors such as hymenialdisine. Alternatively, neurites are blocked if the target KXGS motifs on tau are rendered nonphosphorylatable by point mutations. The results suggest that MARK2 contributes to the plasticity of microtubules needed for neuronal polarity and the growth of neurites.