Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression.

Recent studies have shown that there exists a family of protein kinases structurally and functionally related to the yeast cell cycle regulatory kinase cdc2 [Meyerson, M., Faha, B., Su, L.-K., Harlow, E. & Tsai, L.-H. (1991) Cold Spring Harbor Symp. Quant. Biol. 56, 177-186 and Meyerson, M., Enders, G. H., Wu, C.-L., Su, L.-K., Gorka, C., Nelson, C., Harlow, E. & Tsai, L.-H. (1992) EMBO J. 11, 2909-2917]. Two members of cdc2 family, p34cdc2 (also named cdk1) and cdk2, have been identified in mammalian cells. cdk1 kinase regulates the progression from G2 to M phase, and cdk2 kinase has been proposed to regulate the progression from G1 to S phase. In this work, we have cloned and structurally characterized a third member of the cdc2 kinase family with 58% amino acid sequence identity to mouse cdk1 and 61% identity to human cdk2. We call this kinase neuronal cdc2-like kinase (nclk) because, in contrast to either cdk1 or cdk2, nclk is expressed at high levels in terminally differentiated neurons no longer in the cell cycle. Previous studies have shown [Hisanaga, S., Kusubata, M., Okumura, E. & Kishimoto, T. (1991) J. Biol. Chem. 266, 21798-21803 and Guan, R. J., Hall, F. L. & Cohlberg, J. A. (1992) J. Neurochem. 58, 1365-1371] that cdk1 kinase, but not other structurally defined protein kinases, could phosphorylate the repeated Lys-Ser-Pro (KSP) motifs found in mammalian high and middle molecular mass neurofilament subunits in vitro, but the precise molecular nature of the endogenous neuronal KSP kinase has remained undefined. The structural similarity of nclk to cdk1 kinase and its high level of expression in terminally differentiated neurons suggest that nclk may play a role in the phosphorylation of the neurofilament KSP repeats in vivo, a function distinct from cell cycle regulation. IMAGES:

已有研究表明，存在一类在结构与功能上与酵母细胞周期调控激酶cdc2相关的蛋白激酶家族[Meyerson, M., Faha, B., Su, L.-K., Harlow, E. & Tsai, L.-H. (1991) Cold Spring Harbor Symp. Quant. Biol. 56, 177-186 及 Meyerson, M., Enders, G. H., Wu, C.-L., Su, L.-K., Gorka, C., Nelson, C., Harlow, E. & Tsai, L.-H. (1992) EMBO J. 11, 2909-2917]。在哺乳动物细胞中已鉴定出cdc2家族的两个成员：p34cdc2（亦称为cdk1）与cdk2。cdk1激酶调控细胞周期从G2期向M期的进程，而cdk2激酶被认为调控从G1期向S期的进程。本研究克隆了cdc2激酶家族的第三个成员，并对其结构进行了表征：该激酶与小鼠cdk1的氨基酸序列同源性达58%，与人类cdk2的同源性达61%。我们将该激酶命名为神经元cdc2样激酶（neuronal cdc2-like kinase, nclk），因为与cdk1或cdk2不同，nclk在不再参与细胞周期的终末分化神经元中呈高表达。此前已有研究[Hisanaga, S., Kusubata, M., Okumura, E. & Kishimoto, T. (1991) J. Biol. Chem. 266, 21798-21803 及 Guan, R. J., Hall, F. L. & Cohlberg, J. A. (1992) J. Neurochem. 58, 1365-1371]表明，仅cdk1激酶（而非其他已明确结构的蛋白激酶）可在体外磷酸化哺乳动物高分子量与中分子量神经丝亚基中重复存在的Lys-Ser-Pro（KSP）基序，但内源性神经元KSP激酶的精确分子本质至今仍未明确。nclk与cdk1激酶的结构同源性，以及其在终末分化神经元中的高表达水平，提示nclk可能在体内参与神经丝KSP重复基序的磷酸化过程——这一功能有别于细胞周期调控功能。IMAGES: