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【生命科学】表皮生长因子受体是如何激活的?

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这个帖子发布于14年零9天前，其中的信息可能已发生改变或有所发展。

Researchers Learn How Epidermal Growth Factor Receptor Is Activated
In a discovery that may help scientists design new cancer drugs, Howard Hughes Medical Institute researchers have provided scientists with the first definitive look at how the catalytic center of the epidermal growth factor receptor — a protein often implicated in cancer development — turns itself on to promote cell growth.

The epidermal growth factor receptor (EGFR) is overactive in many breast, lung, colon, and pancreatic cancers. Because of its key role in driving the proliferation of cells, EGFR is a target of several cancer drugs currently in development, as well as several approved therapies. The researchers said their findings offer fresh insight into how these drugs work and clues for the design of the next generation of EGFR inhibitors.

“I suspect the way this worked when the first transmembrane receptors tyrosine kinase evolved was simply to make activation contingent on phosphorylation of one receptor by the other. My suspicion is that as the EGF receptor evolved, it moved away from that primordial mechanism.”
John Kuriyan

The researchers, led by Howard Hughes Medical Institute (HHMI) investigator John Kuriyan, published their findings in the June 15, 2006, issue of the journal Cell. Xuewu Zhang, who is in Kuriyan's laboratory at the University of California, Berkeley, was the first author of the article. Other co-authors were from the Johns Hopkins University School of Medicine.

EGFR is nestled into the cell membrane on the surface of cells. When EGFR is activated by molecules called ligands, members of the EGFR receptor family pair up (dimerize), which then activates a region of the receptor inside the cell called a tyrosine kinase domain, which is the catalytic center of the protein. Kinases are protein switches that activate other proteins by adding a phosphate group to them via a process called phosphorylation.

In healthy cells, EGFR triggers growth in response to an activating signal that comes from outside the cell. When the signal is encountered, EGFR receptors on the surface of the cell form pairs. HHMI researchers have now learned that this pairing causes a physical change in the shape of the kinase domain. This change of shape converts the normally inactive kinase into an active one, which then sends signals inside the cell that trigger cell growth.

“It had long been known that the EGFR ligand dimerizes the receptor and that this dimerization converts into an activation of the kinase domain; but it wasn't understood how that happens,” said Kuriyan. “This paper provides for the first time a very specific and detailed molecular model for how the EGF receptor switches on at the level of the kinase domain.”

In the first set of experiments, the researchers demonstrated that the kinase domain of EGFR is normally maintained in the off state. They found that a particular mutation that activates EGFR in a large percentage of patients with lung cancer caused a 20-fold increase in the kinase domain's activity. And when Zhang forced kinase domains into close proximity to one another — as happens when the receptors dimerize — he found that the kinase switched on. This result suggests that the activation involves some kind of inter-molecular interaction, that is, the kinases activate each other when they are brought together.

The next step was to pinpoint how one EGFR kinase domain would switch on another. A clue came from earlier work by other researchers who were using x-ray crystallography to determine the structure of the kinase domain alone. In x-ray crystallography, protein crystals are bombarded with x-ray beams. As the x-rays pass through and bounce off of atoms in the crystal, they leave a diffraction pattern, which can then be analyzed to determine the three-dimensional shape of the protein.

In their structural studies, those scientists had found only the active conformation of EGFR in their protein crystals. “Those earlier findings made us realize that the crystals must hold the answer to how EGFR switches on,” said Kuriyan.

Thus, Kuriyan and his colleagues performed detailed analyses of the active conformation of this crystal structure and their own new structures. These analyses revealed two types of dimers — a symmetric form, in which both units had the same relative position to each other, and an asymmetric form, in which one unit took a different position relative to the other. Their subsequent experiments determined that the asymmetric conformation was important for activation.

Their studies also determined in structural detail how this activation takes place. They found that the asymmetric activation of one EGFR kinase domain by another is analogous to the activation of cyclin-dependent kinase (CDK) by cyclin, which are involved in regulating cell growth.

“Our model now is that EGFR normally sits in an inactive conformation, which we call Src/CDK-like. But when it is brought into high local concentration — that is, when it's dimerized — that overcomes the barrier for activation through an intermolecular interaction, and one EGFR molecule then pushes the active site of the other into the active state, and that switches it on,” said Kuriyan.

Kuriyan said that the activation mechanism they discovered is more complex than might be expected, but for good evolutionary reason. “When the ligand arrives outside the cell, the receptor has to transmit that information to the inside of the cell. I suspect the way this worked when the first transmembrane receptors tyrosine kinase evolved was simply to make activation contingent on phosphorylation of one receptor by the other. My suspicion is that as the EGF receptor evolved, it moved away from that primordial mechanism.”

Evolution of the more specialized mechanism has ultimately enabled more specific and responsive control of the family of EGFRs. For example, this evolutionary fine-tuning has enabled different combinations of EGFR family members (including ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4) to switch on one another and result in a wide spectrum of specific signals. This kind of specificity is critical to the cell, given the powerful role EGFRs play in cell proliferation, differentiation and migration, Kuriyan noted.

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2006-07-03 01:45 浏览 : 1534 回复 : 2

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• 大龄考研上岸母校，但仍然前途渺茫

atgc

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认领此篇，有些长，慢慢翻译。。。。。。。已经完成。。。。。

研究者探索表皮生长因子活化的机理

在一个可能有助于科学家设计新型抗癌药物的发现中，霍华德•休斯医学研究所的研究者们为科学家提供了第一个关于表皮生长因子受体（一个常与癌症发生）催化中心如何开启自身并促进细胞生长的明确面貌。

在许多乳腺癌、肺癌、结肠癌和胰腺癌症中，表皮生长因子受体是过度活跃的。由于其在驱动细胞增殖中的关键作用，EGFR是现在正在开发的多重抗癌药物的靶点，也是多种已被得到公认的癌症疗法的靶点。研究者们说，他们的发现提供了关于这些药物如何发挥作用的新见解，也为下一代EGRF抑制剂的设计提供了线索。

“当第一个逐步变化的跨膜受体酪氨酸激酶通过一个受体被另外一个受体磷酸化而轻易实现临时激活时，我怀疑这种作用方式。我的假设是这样的，当EGF受体逐渐变化时，它从起始的结构中移动开了”， John Kuriyan说。

由霍华德•休斯医学研究所研究者John Kuriyan领导的研究者，再2006年6月15日出版的那期Cell杂志上发表了他们的发现。在加州大学伯克里分校Kuriyan实验室的Xuewu Zhang是该论文的第一作者。其他共同作者都来自约翰霍普金斯大学医学院。

EGRF镶嵌在细胞表面的细胞膜中。当EGFR被称为配体的分子激活时，EGFR受体家族成员配对（二聚化），随后激活了位于细胞内的受体上一个被称为酪氨酸激酶结构域的区域，也就是该蛋白的催化中心。激酶是蛋白开关，它们通过一个称为磷酸化的过程将磷酸基团结合到其他蛋白上并激活这些蛋白。

在健康细胞中，EGFR通过感应来自细胞外的激活信号激发细胞生长。当遇到信号时，细胞表面的EGFR受体配对。霍华德•休斯医学研究所的研究人员现已经得知，这种配对导致了激酶结构域形状上的物理变化。这种形状上的变化将通常状况下无活性的激酶转变为活性形式，随后将能够激发细胞生长的信号传递到胞内。

“人们很早就知道，EGFR配体使受体二聚化，这种二聚化导致激酶结构域的激活；但是，对于其发生的过程却并不了解”， Kuriyan说，“这个论文第一次为EGF受体在激酶结构域的水平上开启的机理提供了一个非常特异而详尽的分子模型”。

在试验的第一阶段，研究者证明，EGFR的激酶结构域在通常情况下处于关闭的状态。他们发现，在较大比例患有肺癌的病人中，可以激活EGFR的特定突变能导致激酶结构域活性增加20倍。当Xuewu Zhang迫使一个激酶结构域与另外一个结构域靠得很近时——当受体二聚化时会产生这样的情形——他发现，激酶开启。这个结果表明，激活涉及一些分子间的相互作用，也就是说，当激酶到一起时，它们相互激活。

下一步是精确地研究一个EGFR激酶结构域是如何开启另外一个激酶的。一个线索是来自利用X－光晶体学方法确定单一激酶结构域结构的其他研究者先前的工作。在X－光晶体学中，用X－光束轰击蛋白质晶体。当X－光通过并从晶体内的原子上反弹时，它们会留下一个衍射的图案，对这种衍射图案的分析可以用于确定蛋白质的三维结构。

在他们的结构研究中，这些科学家已经发现，在他们制备的蛋白质晶体中，只存在活性构象的EGFR。“这些早期的发现使我们意识到，回答EGFR如何开启的答案肯定在该蛋白质的晶体结构中”， Kuriyan说。

因此，Kuriyan和他的合作者对该晶体结构的活性构象和他们自己获得的新的蛋白结构进行了详细的分析。这些分析揭示了两种类型的二聚体：对称型和不对称型。在对称型结构中，两个分子具有相同的相对于对方的位置。在不对称型结构中，一个分子的位置与另外一个分子的位置不同。他们接下去的试验证实了不对称型构象对激活的是重要的。

他们的研究也在结构细节上确定了这种激活作用是如何发生的。他们发现，由一个分子对另外一个EGFR激酶结构域的不对称激活类似于涉及调控细胞生长的细胞周期蛋白激活细胞周期蛋白依赖型激酶的方式。

“在我们的模型中，EGFR通常处于无活性构象，我们称之为类Src/CDK型。但是，当它处于可以克服通过分子间相互作用而激活所必须跨越的障碍的局部高浓度时，也就是当它们二聚化时，一个EGFR分子推动另外一个分子的活性中心使其成为活性状态，也就是开启了该分子”， Kuriyan说。

Kuriyan说，除了进化的原因，他们揭示的激活机制比预期的更为复杂。（这个句子搞不准，请教版主！）“当配体到达细胞外时，受体必须将该信息传递到细胞内。当第一个逐步变化的跨膜受体酪氨酸激酶通过一个受体被另外一个受体磷酸化而轻易实现临时激活时，我怀疑这种作用方式。我的假设是这样的，当EGF受体逐渐变化时，它从起始的结构中移动开了”。

更专化的作用机制的进化最终使更加特异而具有高度响应能力的EGFR家族的控制成为可能。例如，这种进化上的微调使EGFR家族成员出现不同的组合（包括ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4）以实现一个个的开启，并实现对大量特异性信号响应。Kuriyan指出，考虑到EGFR在细胞增殖分化和迁移中所扮演的重要角色，这种特异性对细胞来说是至关重要的。

2006-07-03 10:34

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atgc 编辑于 2006-07-03 18:07

• AVF血栓介入治疗中肘部穿静脉栓塞的处理

bingranzi2001

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有没有一些EGFR与其他一些受体的作用的呢

2011-06-11 11:33

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