Kortenjann M, Shaw P E
Max-Planck-Institute für Immunbiologie, Spemann Laboratories, Freiburg, Germany.
Crit Rev Oncog. 1995;6(2):99-115.
The family of MAP kinases consists of several subgroups of serine/threonine protein kinases. Together with their activating kinases, they function to regulate cellular responses to diverse extracellular signals, including osmotic stress, heat shock, proinflammatory cytokines, and mitogens. It is now clear that as in yeast, separate MAP kinase cascades exist in mammalian cells, responding selectively to different stimuli by phosphorylating cytoplasmic components and nuclear transcription factors. Down-regulation of MAP kinase pathways may occur through dephosphorylation by serine/threonine phosphatases, tyrosine phosphatases, or dual-specificity phosphatases and through feedback inhibitory mechanisms that involve the phosphorylation of upstream kinases. The functional integrity of each MAP kinase cascade is thought to be established and maintained by specific molecular interactions both between the kinases and with cytoplasmic anchors that nucleate complex formation. The recent demonstration that a series of pyridinyl-imidazole compounds can bind and inhibit certain MAP kinases suggests that other MAP kinase subgroups may also be susceptible to synthetic compounds. Drugs that selectively down-regulate MAP kinase cascades could prove to be valuable as therapeutic agents in the control of malignant disease.
丝裂原活化蛋白激酶（MAP激酶）家族由几个丝氨酸/苏氨酸蛋白激酶亚组组成。它们与激活激酶一起，发挥作用以调节细胞对多种细胞外信号的反应，包括渗透压应激、热休克、促炎细胞因子和有丝分裂原。现在很清楚，与酵母一样，哺乳动物细胞中存在独立的MAP激酶级联反应，通过磷酸化细胞质成分和核转录因子来选择性地响应不同的刺激。MAP激酶途径的下调可能通过丝氨酸/苏氨酸磷酸酶、酪氨酸磷酸酶或双特异性磷酸酶的去磷酸化，以及涉及上游激酶磷酸化的反馈抑制机制来实现。每个MAP激酶级联反应的功能完整性被认为是通过激酶之间以及与形成复合物核心的细胞质锚定物之间的特定分子相互作用来建立和维持的。最近有证据表明，一系列吡啶基咪唑化合物可以结合并抑制某些MAP激酶，这表明其他MAP激酶亚组也可能对合成化合物敏感。选择性下调MAP激酶级联反应的药物可能被证明是控制恶性疾病的有价值的治疗剂。
