【原】MAPK/ERK信号通路

MAPK, mitogen-activated protein kinases (MAPKs) are a class of serine/threonine protein kinases (serine/threonine kinases) in cells, which can phosphorylate some target proteins with serine threonine.

MAPK，丝裂原活化蛋白激酶(mitogen-activated　protein　kinases，MAPKs)是细胞内的一类丝氨酸/苏氨酸蛋白激酶，可以使一些带有丝氨酸苏氨酸的靶标蛋白发生磷酸化。

MAPKs signal transduction pathway exists in most cells, which can transfer extracellular signal to cells and their nuclei, and cause cell proliferation, differentiation, transformation and apoptosis.

MAPKs信号转导通路存在于大多数细胞内，在将细胞外刺激信号转导至细胞及其核内，并引起细胞增殖、分化、转化及凋亡等。

The MAPKs signal transduction pathway is highly conserved in evolution. Several parallel MAPKs signaling pathways have been identified, and different extracellular stimuli can use different MAPKs signaling pathways.

MAPKs信号转导通路在进化上高度保守。目前已发现多条并行的MAPKs信号通路，不同的细胞外刺激可使用不同的MAPKs信号通路。

Erk (extraneous signal-regulated Kinase) signal pathway:

ERK(extracellular signal-regulated kinase)信号通路 ：

　

MAPK first reported by Sturgill et Al. , 1986. Its name was initially confusing, referring to substrate proteins as MAP2K, Erk, MBPK, RSKK, Ertk, and so on. Since then, because it was found to have the same structural and biochemical characteristics, and was named MAPK. With the discovery of different MAPK family members, it was renamed ERK again.

　

1986年由Sturgill等人首先报告的MAPK。最初其名称十分混乱，曾根据底物蛋白称之为MAP2K、ERK、MBPK、RSKK、ERTK等。此后，由于发现其具有共同的结构和生化特征，而被命名为MAPK。随着不同MAPK家族成员的发现，又重新改称为ERK。

In mammalian cells, the ERK-related intracellular signal transduction pathway is considered as a classical MAPK signal transduction pathway, and its activation process and biological significance have been well understood. Studies have confirmed that receptor tyrosine Kinase, g protein coupled receptors and part of the Cytokine receptor can activate the ERK signal transduction pathway.

哺乳类动物细胞中，与ERK相关的细胞内信号转导途径被认为是经典MAPK信号转导途径，目前对其激活过程及生物学意义已有了较深入的认识。研究证实，受体酪氨酸激酶、G蛋白偶联的受体和部分细胞因子受体均可激活ERK信号转导途径。

For example:

1.  Growth factor binds to a specific receptor on the cell membrane, causing the receptor to form dimers

2. The dimerization receptor activates its own tyrosine kinase;

3. The phosphorylated tyrosine on the receptor binds to the SH2 domain of the growth factor receptor binding protein 2(GRB2) on the cell membrane

4. The SH3 domain of GRB2 is also associated with Guanine Nucleotide Exchange factor, which dissociates the GDP of small molecule G protein Ras to GTP, thus activating Ras

5. The activated Ras further binds to the Amino terminus of the Ser/threonine protein kinase Raf-1 and activates Raf-1 through an unknown mechanism

6. RAF-1 phosphorylated two regulatory serines on MEK1/MEK2(MAP kinase/ERK Kinase) to activate meks;

7. MEKs, a double-specific kinase, phosphorylates serine/threonine and tyrosine, and highly selectively activates ERK1 and Erk2(P44MAPK and P42MAPK)

8. ERKs is a proline-directed Ser/threonine kinase that phosphorylates silk/threonine adjacent to proline. After mitogen stimulation, ERKs receives upstream cascade response signals that can be transposed into the nucleus.

如：

1. 生长因子与细胞膜上的特异受体结合，可使受体形成二聚体;
2. 二聚化的受体使其自身酪氨酸激酶被激活; 
3. 受体上磷酸化的酪氨酸又与位于胞膜上的生长因子受体结合蛋白2(Grb2)的SH2结构域相结合;
4. 而Grb2的SH3结构域则同时与鸟苷酸交换因子SOS(Son　of　Sevenless)结合，后者使小分子鸟苷酸结合蛋白Ras的GDP解离而结合GTP，从而激活Ras; 
5. 激活的Ras进一步与丝/苏氨酸蛋白激酶Raf-1的氨基端结合，通过未知机制激活Raf-1; 
6. Raf-1可磷酸化MEK1/MEK2(MAP　kinase/ERK　kinase)上的二个调节性丝氨酸，从而激活MEKs;
7. MEKs为双特异性激酶，可以使丝/苏氨酸和酪氨酸发生磷酸化，最终高度选择性地激活ERK1和ERK2(即p44MAPK和p42MAPK)。
8. ERKs为脯氨酸导向的丝/苏氨酸激酶，可以磷酸化与脯氨酸相邻的丝/苏氨酸。在丝裂原刺激后，ERKs接受上游的级联反应信号，可以转位进入细胞核。

ERKs not only phosphorylated cytosolic proteins, but also phosphorylated some nuclear transcription factors such as c-fos, C-jun, Elk-1, c-myc and ATF2, thus participating in the regulation of cell proliferation and differentiation.

因此，ERKs不仅可以磷酸化胞浆蛋白，而且可以磷酸化一些核内的转录因子如c-fos、c-Jun、Elk-1、c-myc和ATF2等，从而参与细胞增殖与分化的调控。

In addition, Erk also phosphorylated Erks Pathway, whose upstream proteins such as NGF receptor, SOS, Raf-1, Mek, and so on. Then, the pathway is adjusted by its own negative feedback.

另外，ERK还可以磷酸化ERKs通路 的上游蛋白如NGF受体、SOS、Raf-1、MEK等，进而对该通路进行自身的负反馈调节。

It has also been found that Erks phosphorylates cytoskeleton components in the CYTOPLASM, such as microtubule-associated protein, MAP-2 and Map-4, which are involved in the regulation of cell morphology and the redistribution of Cytoskeleton.

还有研究发现，ERKs可磷酸化胞浆内的细胞骨架成份，如微管相关蛋白MAP-1、MAP-2和MAP-4，参与细胞形态的调节及细胞骨架的重分布。

Recently, foreign researchers have cloned ERK5 and its upstream kinase MEK5. The MAPKs signal pathway can be activated by H2O2 and hyperosmotic stimulation, and its substrate is C-MYC. It was found that ERK3 Kinase/ERK3 and ERK4 existed by molecular biology technology, but the activation signal, substrate and biological significance of Erk3 Kinase/ERK3 and Erk4 were not clear.

最近，国外学者又新克隆出ERK5及其上游激酶MEK5，这条MAPKs信号通路可被H2O2及高渗激活，其底物为c-Myc。通过分子生物学技术发现还有ERK3 Kinase/ERK3及ERK4两条通路存在，但目前对其激活信号、底物及生物学意义还不清楚。