Sweatt J D
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030-3498, USA.
J Neurochem. 2001 Jan;76(1):1-10. doi: 10.1046/j.1471-4159.2001.00054.x.
The mitogen-activated protein kinase (MAP kinase, MAPK) cascade, as the name implies, was originally discovered as a critical regulator of cell division and differentiation. As further details of this signaling cascade were worked out, it became clear that the MAPK cascade is in fact a prototype for a family of signaling cascades that share the motif of three serially linked kinases regulating each other by sequential phosphorylation. Thus, a revised nomenclature arose that uses the term MAPK to refer to the entire superfamily of signaling cascades (comprising the erks, the JNKs and the p38 stress activated protein kinases), and specifies the prototype MAPK as the extracellular signal-regulated kinase (erk). The two erk MAPK isoforms, p44 MAPK and p42 MAPK, are referred to as erk1 and erk2, respectively. The erks are abundantly expressed in neurons in the mature central nervous system, raising the question of why the prototype molecular regulators of cell division and differentiation are present in these non-dividing, terminally differentiated neurons. This review will describe the beginnings of an answer to this question. Interestingly, the general model has begun to emerge that the erk signaling system has been co-opted in mature neurons to function in synaptic plasticity and memory. Moreover, recent insights have led to the intriguing prospect that these molecules serve as biochemical signal integrators and molecular coincidence detectors for coordinating responses to extracellular signals in neurons. In this review I will first outline the essential components of this signal transduction cascade, and briefly describe recent results implicating the erks in mammalian synaptic plasticity and learning. I will then proceed to outline recent results implicating the erks as molecular signal integrators and, potentially, coincidence detectors. Finally, I will speculate on what the critical downstream effectors of the erks are in neurons, and how they might provide a readout of the integrated signal.
丝裂原活化蛋白激酶（MAP激酶，MAPK）级联反应，顾名思义，最初是作为细胞分裂和分化的关键调节因子被发现的。随着对这一信号级联反应更多细节的深入研究，人们清楚地认识到，MAPK级联反应实际上是一类信号级联反应家族的原型，这类家族共享由三个串联激酶通过顺序磷酸化相互调节的基序。因此，出现了一种修订后的命名法，用MAPK一词指代信号级联反应的整个超家族（包括细胞外调节蛋白激酶（ERK）、应激活化蛋白激酶（JNK）和p38应激激活蛋白激酶），并将原型MAPK指定为细胞外信号调节激酶（ERK）。两种ERK MAPK同工型，p44 MAPK和p42 MAPK，分别被称为ERK1和ERK2。ERK在成熟中枢神经系统的神经元中大量表达，这就引发了一个问题：为什么细胞分裂和分化的原型分子调节因子会存在于这些不分裂、终末分化的神经元中。本综述将阐述对这个问题的初步答案。有趣的是，一个普遍的模型已经开始浮现，即ERK信号系统在成熟神经元中被用于发挥突触可塑性和记忆方面的功能。此外，最近的见解引发了一个有趣的前景，即这些分子作为生化信号整合器和分子巧合探测器，用于协调神经元对细胞外信号的反应。在本综述中，我将首先概述这一信号转导级联反应的基本组成部分，并简要描述最近表明ERK参与哺乳动物突触可塑性和学习的研究结果。然后，我将继续概述最近表明ERK作为分子信号整合器以及潜在的巧合探测器的研究结果。最后，我将推测ERK在神经元中的关键下游效应器是什么，以及它们如何可能提供整合信号的读数。
