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通过工程化化学遗传学控制其活性来解析蛋白酪氨酸磷酸酶信号转导。

Dissecting protein tyrosine phosphatase signaling by engineered chemogenetic control of its activity.

机构信息

Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL.

Argonne National Laboratory, Lemont, IL.

出版信息

J Cell Biol. 2022 Aug 1;221(8). doi: 10.1083/jcb.202111066. Epub 2022 Jul 13.

DOI:10.1083/jcb.202111066
PMID:35829702
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9284425/
Abstract

Protein tyrosine phosphatases (PTPases) are critical mediators of dynamic cell signaling. A tool capable of identifying transient signaling events downstream of PTPases is essential to understand phosphatase function on a physiological time scale. We report a broadly applicable protein engineering method for allosteric regulation of PTPases. This method enables dissection of transient events and reconstruction of individual signaling pathways. Implementation of this approach for Shp2 phosphatase revealed parallel MAPK and ROCK II dependent pathways downstream of Shp2, mediating transient cell spreading and migration. Furthermore, we show that the N-SH2 domain of Shp2 regulates MAPK-independent, ROCK II-dependent cell migration. Engineered targeting of Shp2 activity to different protein complexes revealed that Shp2-FAK signaling induces cell spreading whereas Shp2-Gab1 or Shp2-Gab2 mediates cell migration. We identified specific transient morphodynamic processes induced by Shp2 and determined the role of individual signaling pathways downstream of Shp2 in regulating these events. Broad application of this approach is demonstrated by regulating PTP1B and PTP-PEST phosphatases.

摘要

蛋白酪氨酸磷酸酶（PTPases）是动态细胞信号转导的关键介质。一种能够识别 PTPases 下游瞬时信号事件的工具对于在生理时间尺度上理解磷酸酶功能至关重要。我们报告了一种广泛适用于 PTPase 变构调节的蛋白质工程方法。该方法能够剖析瞬时事件并重建单个信号通路。该方法在 Shp2 磷酸酶中的实施揭示了 Shp2 下游平行的 MAPK 和 ROCK II 依赖途径，介导瞬时细胞扩展和迁移。此外，我们表明 Shp2 的 N-SH2 结构域调节 MAPK 非依赖性、ROCK II 依赖性细胞迁移。Shp2 活性针对不同蛋白质复合物的工程靶向表明，Shp2-FAK 信号诱导细胞扩展，而 Shp2-Gab1 或 Shp2-Gab2 介导细胞迁移。我们确定了由 Shp2 诱导的特定瞬时形态动力学过程，并确定了 Shp2 下游的各个信号通路在调节这些事件中的作用。通过调节 PTP1B 和 PTP-PEST 磷酸酶，证明了该方法的广泛适用性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/b24154894504/JCB_202111066_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/4b11426d6c49/JCB_202111066_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/64b194990a08/JCB_202111066_Fig2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/acc46cf9ef9e/JCB_202111066_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/b0d4c13f1787/JCB_202111066_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/b587909dcc26/JCB_202111066_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/c8bcc0905997/JCB_202111066_FigS2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/0d3d343d63eb/JCB_202111066_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/a3b3fa22752a/JCB_202111066_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/660d87bffade/JCB_202111066_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/c75109537cfb/JCB_202111066_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/c46b86d81af9/JCB_202111066_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/b24154894504/JCB_202111066_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/4b11426d6c49/JCB_202111066_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/64b194990a08/JCB_202111066_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/9cbe2860bbc8/JCB_202111066_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/acc46cf9ef9e/JCB_202111066_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/b0d4c13f1787/JCB_202111066_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/b587909dcc26/JCB_202111066_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/c8bcc0905997/JCB_202111066_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/6f57ea521fa1/JCB_202111066_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/53f11add48a1/JCB_202111066_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/0d3d343d63eb/JCB_202111066_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/a3b3fa22752a/JCB_202111066_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/660d87bffade/JCB_202111066_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/c75109537cfb/JCB_202111066_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/c46b86d81af9/JCB_202111066_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/de70/9284425/b24154894504/JCB_202111066_Fig10.jpg

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引用本文的文献

[1]
Deep mutational scanning of the multi-domain phosphatase SHP2 reveals mechanisms of regulation and pathogenicity.

Nat Commun. 2025-7-1

[2]
Development and Application of Rapamycin-regulated Tyrosine Phosphatases.

J Vis Exp. 2024-9-6

[3]
Non-receptor Type PTPases and their Role in Controlling Pathways Related to Diabetes and Liver Cancer Signalling.

Curr Pharm Biotechnol. 2025

本文引用的文献

[1]
An allosteric interaction controls the activation mechanism of SHP2 tyrosine phosphatase.

Sci Rep. 2020-10-28

[2]
Phosphatase-independent functions of SHP2 and its regulation by small molecule compounds.

J Pharmacol Sci. 2020-8-3

[3]
Scalable molecular dynamics on CPU and GPU architectures with NAMD.

J Chem Phys. 2020-7-28

[4]
Structural Determinants of Phosphopeptide Binding to the N-Terminal Src Homology 2 Domain of the SHP2 Phosphatase.

J Chem Inf Model. 2020-6-22

[5]
Minimally disruptive optical control of protein tyrosine phosphatase 1B.

Nat Commun. 2020-2-7

[6]
A specific amino acid context in EGFR and HER2 phosphorylation sites enables selective binding to the active site of Src homology phosphatase 2 (SHP2).

J Biol Chem. 2020-2-4

[7]
Targeting SHP2 as a promising strategy for cancer immunotherapy.

Pharmacol Res. 2019-12-12

[8]
Gain-Of-Function E76K-Mutant SHP2 Promotes Cell Proliferation, Metastasis, And Tumor Growth In Glioblastoma Through Activation Of The ERK/CREB Pathway.

Onco Targets Ther. 2019-11-7

[9]
Shp2 expression is upregulated in cervical cancer, and Shp2 contributes to cell growth and migration and reduces sensitivity to cisplatin in cervical cancer cells.

Pathol Res Pract. 2019-9-3

[10]
Protein tyrosine phosphatase 11 acts through RhoA/ROCK to regulate eosinophil accumulation in the allergic airway.

FASEB J. 2019-7-30

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