THE STRESS-ACTIVATED PROTEIN-KINASE SUBFAMILY OF C-JUN KINASES
THE STRESS-ACTIVATED PROTEIN-KINASE SUBFAMILY OF C-JUN KINASES
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DOI：
10.1038/369156a0
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发表时间：
1994-05-12
期刊：
影响因子：
64.8
通讯作者：
WOODGETT, JR
中科院分区：
文献类型：
--
作者：
KYRIAKIS, JM;BANERJEE, P;WOODGETT, JR
有丝分裂原活化蛋白（MAP）激酶Erk-1和Erk-2是脯氨酸导向的激酶，它们本身通过伴随的酪氨酸和苏氨酸残基磷酸化而被激活（1-4）。激酶p54（M（r）54，000）首先从环己酰亚胺处理的大鼠中分离，与Erks-1/2一样是脯氨酸导向的，并且需要Tyr和Ser/Thr磷酸化才能具有活性（3，5，6）。然而，p54与Erks-1/2的底物特异性不同，不能磷酸化pp 90（rsk），但在磷酸化c-Jun反式激活结构域中更活跃（5，7，8）。p54的分子克隆揭示了细胞外调节激酶的一个独特亚家族。虽然它们与Erks-1/2的序列有40-45%的相同性，但与Erks-1/2不同的是，p54在大多数细胞中仅被有丝分裂原或佛波醇酯弱激活。然而，p54是由细胞应激和肿瘤坏死因子（TNF）-α激活的主要c-Jun N-末端激酶，因此它们被称为应激激活蛋白激酶或SAPK。SAPKs也被鞘磷脂酶激活，鞘磷脂酶引起对TNF-α的细胞应答的子集（参考文献9）。因此，SAPKs定义了一种新的TNF-α和应激激活的信号通路，可能由基于鞘磷脂的第二信使启动，其调节c-Jun的活性。
THE mitogen-activated protein (MAP) kinases Erk-1 and Erk-2 are proline-directed kinases that are themselves activated through concomitant phosphorylation of tyrosine and threonine residues(1-4). The kinase p54 (M(r) 54,000), which was first isolated from cycloheximide-treated rats, is proline-directed like Erks-1/2, and requires both Tyr and Ser/Thr phosphorylation(3,5,6) for activity. p54 is, however, distinct from Erks-1/2 in its substrate specificity, being unable to phosphorylate pp90(rsk) but more active in phosphorylating the c-Jun transactivation domain(5,7,8). Molecular cloning of p54 reveals a unique subfamily of extracellularly regulated kinases. Although they are 40-45% identical in sequence to Erks-1/2, unlike Erks-1/2 the p54s are only poorly activated in most cells by mitogens or phorbol esters. However, p54s are the principal c-Jun N-terminal kinases activated by cellular stress and tumour necrosis factor (TNF)-alpha, hence they are designated stress-activated protein kinases, or SAPKs. SAPKs are also activated by sphingomyelinase, which elicits a subset of cellular responses to TNF-alpha (ref. 9). SAPKs therefore define a new TNF-alpha and stress-activated signalling pathway, possibly initiated by sphingomyelin-based second messengers, which regulates the activity of c-Jun.