Grb2 monomer-dimer equilibrium determines normal versus oncogenic function.
Grb2 monomer-dimer equilibrium determines normal versus oncogenic function.
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DOI：
10.1038/ncomms8354
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发表时间：
2015-06-24
影响因子：
16.6
通讯作者：
Ladbury JE
中科院分区：
文献类型：
--
作者：
Ahmed Z;Timsah Z;Suen KM;Cook NP;Lee GR 4th;Lin CC;Gagea M;Marti AA;Ladbury JE
适配蛋白生长因子受体结合蛋白2 （Grb2）在真核细胞中普遍表达，并参与多种细胞内蛋白相互作用。Grb2在酪氨酸激酶介导的信号转导中起着关键作用，包括将受体酪氨酸激酶连接到Ras/丝裂原活化蛋白（MAP）激酶途径，这与致癌结果有关。Grb2存在于单体和二聚体状态之间的本构平衡。在这里，我们发现只有单体Grb2能够与SOS结合并上调MAP激酶信号，而二聚体状态对这一过程具有抑制作用。Grb2上酪氨酸160 （Y160）的磷酸化，或含有酪氨酸磷酸酯的配体与Grb2的SH2结构域结合，导致二聚体解离。Y160在Grb2上的磷酸化很容易在人类前列腺癌、结肠癌和乳腺癌的恶性形式中检测到。Grb2的自结合/解离代表了一个调节MAP激酶活性的开关，从而控制癌症的进展。Grb2是一种接头蛋白，可以作为二聚体存在，在Y160磷酸化时解离。在这里，作者表明，只有单体蛋白能够激活有丝分裂原激活的蛋白激酶信号转导，从而控制致癌结果。
The adaptor protein growth factor receptor-bound protein 2 (Grb2) is ubiquitously expressed in eukaryotic cells and involved in a multitude of intracellular protein interactions. Grb2 plays a pivotal role in tyrosine kinase-mediated signal transduction including linking receptor tyrosine kinases to the Ras/mitogen-activated protein (MAP) kinase pathway, which is implicated in oncogenic outcome. Grb2 exists in a constitutive equilibrium between monomeric and dimeric states. Here we show that only monomeric Grb2 is capable of binding to SOS and upregulating MAP kinase signalling and that the dimeric state is inhibitory to this process. Phosphorylation of tyrosine 160 (Y160) on Grb2, or binding of a tyrosylphosphate-containing ligand to the SH2 domain of Grb2, results in dimer dissociation. Phosphorylation of Y160 on Grb2 is readily detectable in the malignant forms of human prostate, colon and breast cancers. The self-association/dissociation of Grb2 represents a switch that regulates MAP kinase activity and hence controls cancer progression. Grb2 is an adaptor protein that can exist as a dimer that dissociates on phosphorylation of Y160. Here, the authors show that only the monomeric protein is capable of activating mitogen-activated protein kinase signal transduction and hence control oncogenic outcome.
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影响因子：
4.1
作者：
Schueller, Annika C.;Ahmed, Zamal;Ladbury, John E.
通讯作者：
Ladbury, John E.
影响因子：
11.4
作者：
Ong, SH;Dilworth, S;Kiefer, F
通讯作者：
Kiefer, F
影响因子：
5.3
作者：
GHOSH, J;MILLER, RA
通讯作者：
MILLER, RA
影响因子：
11.4
作者：
Li, SG;Couvillon, AD;Van Etten, RA
通讯作者：
Van Etten, RA
影响因子：
56.9
作者：
MAIGNAN, S;GUILLOTEAU, JP;DUCRUIX, A
通讯作者：
DUCRUIX, A