Ectoprotein Kinase in the Regulation of Cellular Responsiveness to Extracellular ATP a
Ectoprotein Kinase in the Regulation of Cellular Responsiveness to Extracellular ATP a
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胞外蛋白激酶调节细胞对细胞外 ATP 的反应
DOI：
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发表时间：
1990
影响因子：
5.2
通讯作者：
E. Kornecki
中科院分区：
文献类型：
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作者：
Y. Ehrlich;M. V. Hogan;Z. Pawłowska;Ulhaus Naik;E. Kornecki
细胞内蛋白质的可逆磷酸化已被确定为许多细胞功能的关键调节机制。在这个过程中，酶蛋白激酶转移三磷酸腺苷的伽马磷酸，与特定的蛋白质形成共价键。另一项研究表明，胞外ATP在各种细胞系统中是一种强大的生理调节因子。尽管胞外ATP的许多生理效应是由嘌呤能受体介导的，但胞外蛋白磷酸化系统也可能参与了细胞对胞外ATP的反应机制。胞外蛋白激酶在各种细胞表面的鉴定为这种机制的存在提供了证据，并揭示了蛋白质磷酸化系统的调节能力如何延伸到细胞外环境。胞外蛋白磷酸化活性在细胞功能调节中可能发挥的多种作用被细胞表面这种活性的多个蛋白质底物的存在所强调。每一种这样的表面磷蛋白都可能具有独特的功能。图5描述了胞吐作用分泌的细胞外ATP与这些分泌神经元的特定生理功能之间的假设关系。根据本文的研究结果，我们认为胞外的ATP可以被两种类型的胞外蛋白激酶利用：膜结合的胞外蛋白激酶和可溶性的胞外蛋白激酶。外源蛋白激酶可以由胞外蛋白从细胞表面分离而来，也可以是一种胞内蛋白，通过胞吐作用从刺激细胞中与三磷酸腺苷共同释放。分泌细胞表面特定蛋白质的磷酸化可能对其自身的突触前活动具有重要的反馈控制作用。胞外蛋白激酶可以通过磷酸化参与分泌的离子通道和/或通过磷酸化转运蛋白实现释放的递质分子的重新摄取来实施这种反馈调节。受体的磷酸化可以调节细胞间的通讯，整合素的磷酸化可以调节细胞表面与细胞外基质成分的相互作用。尽管图5中提出的大多数关系仍然是假设的，但应该可以通过提高针对特定表面磷蛋白的磷酸化位点的抗体，以直接的实验方式对它们进行测试。这种抗体在不穿透细胞的情况下抑制蛋白质磷酸化的能力为直接测试各种细胞中胞外和外源蛋白激酶活性的潜在生理功能提供了一个实验范例。
The reversible phosphorylation of intracellular proteins has been established as a key regulatory mechanism in numerous cellular functions. In this process the enzyme protein kinase transfers the gamma-phosphate of ATP to form a covalent bond with specific proteins. Another line of investigation has demonstrated that extracellular ATP is a potent physiological regulator in various cellular systems. Although many of the physiological effects of extracellular ATP were shown to be mediated by the action of purinergic receptors, it is possible that extracellular protein phosphorylation systems are also implicated in the mechanisms underlying the responsiveness of cells to extracellular ATP. The identification of ectoprotein kinase at the surface of various cells has provided evidence for the existence of such mechanisms, and revealed how the regulatory powers of protein phosphorylation systems can extend to the extracellular environment. The versatile roles that extracellular protein phosphorylation activity may play in the regulation of cellular functions is underscored by the presence of multiple protein substrates for this activity at the cell surface. Each such surface phosphoprotein may have a unique function. FIGURE 5 depicts the hypothetical relationships between the extracellular ATP secreted by exocytosis and the specific physiological function of these secreting neurons. Based on findings described in this article, we propose that extracellular ATP can be utilized by two types of extracellular protein kinase: a membrane-bound ectoprotein kinase, and a soluble exoprotein kinase. The exoprotein kinase can originate by detachment of an ectokinase from the cell surface, or be an intravesicular protein that is coreleased with ATP by exocytosis from stimulated cells. Phosphorylation of specific proteins at the surface of a secreting cell may have an important feedback control over its own presynaptic activity. The ectoprotein kinase could exert this feedback regulation by phosphorylating ion channels involved in secretion, and/or by phosphorylating transporters that carry out the reuptake of released transmitter molecules. Phosphorylation of receptors can regulate intercellular communication, and phosphorylation of integrins could regulate the interaction of the cell surface with components of the extracellular matrix. Although most of the relationships suggested in FIGURE 5 are still hypothetical, it should be possible to test them experimentally in a direct manner by raising antibodies against the phosphorylated sites of specific surface phosphoproteins. The ability of such antibodies to inhibit protein phosphorylation without penetrating the cells provides an experimental paradigm for the direct testing of potential physiological function of ecto- and exoprotein kinase activities in a variety of cells.