pH sensing by FAK-His58 regulates focal adhesion remodeling.
pH sensing by FAK-His58 regulates focal adhesion remodeling.
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DOI：
10.1083/jcb.201302131
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发表时间：
2013-09-16
期刊：
影响因子：
--
通讯作者：
Barber DL
中科院分区：
文献类型：
--
作者：
Choi CH;Webb BA;Chimenti MS;Jacobson MP;Barber DL
FAK-His 58可感知细胞内pH升高，促进FAK自磷酸化和粘着斑重塑。细胞内pH（pHi）动态调节不同的细胞过程，包括局部粘连的重塑。我们现在报告，粘着斑激酶（FAK），一个关键的调节局灶性粘连重塑，是一个pH传感器响应生理变化的pH值。FAK激活的第一步是Tyr 397的自磷酸化，这增加了较高的pH值。我们使用了一种基因编码的生物传感器，以显示在细胞扩散过程中，随着粘着斑的成熟，粘着斑的pH值会增加。我们还表明，具有降低的pHi的细胞具有减弱的FAK-pY 397以及有缺陷的细胞铺展和粘着斑。诱变研究表明FAK-His 58对pH传感至关重要，分子动力学模拟表明His 58去质子化驱动构象变化的模型，可能调节Tyr 397的自磷酸化可及性。FAK-H58 A在成纤维细胞中的表达足以在低pHi下恢复有缺陷的自磷酸化和细胞铺展。这些数据与理解癌症转移相关，癌症转移依赖于增加的pHi和FAK活性。
Increased intracellular pH is sensed by FAK-His58, which facilitates FAK autophosphorylation and focal adhesion remodeling. Intracellular pH (pHi) dynamics regulates diverse cellular processes, including remodeling of focal adhesions. We now report that focal adhesion kinase (FAK), a key regulator of focal adhesion remodeling, is a pH sensor responding to physiological changes in pH. The initial step in FAK activation is autophosphorylation of Tyr397, which increased with higher pHi. We used a genetically encoded biosensor to show increased pH at focal adhesions as they mature during cell spreading. We also show that cells with reduced pHi had attenuated FAK-pY397 as well as defective cell spreading and focal adhesions. Mutagenesis studies indicated FAK-His58 is critical for pH sensing and molecular dynamics simulations suggested a model in which His58 deprotonation drives conformational changes that may modulate accessibility of Tyr397 for autophosphorylation. Expression of FAK-H58A in fibroblasts was sufficient to restore defective autophosphorylation and cell spreading at low pHi. These data are relevant to understanding cancer metastasis, which is dependent on increased pHi and FAK activity.
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DOI：
10.1083/jcb.133.6.1391
发表时间：
1996-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Demaurex N;Downey GP;Waddell TK;Grinstein S
通讯作者：
Grinstein S
影响因子：
2.9
作者：
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通讯作者：
Friesner, RA
影响因子：
10.5
作者：
McLean, GW;Komiyama, NH;Frame, MC
通讯作者：
Frame, MC
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
20.1
作者：
Ilic, D;Kovacic, B;Damsky, CH
通讯作者：
Damsky, CH