Integrin β3E726 Regulates the Switch Between Platelet Spreading and Clot Retraction by Interfering Gα13/RhoA Pathway

Platelet spreading and clot retraction, albeit both mediated by integrin outside-in signaling, lead to platelet shape changes in two opposite directions. The mechanisms by which these processes are regulated are not fully understood. Our previous study found that E726Q mutation in β3 integrin caused impaired spreading in Chinese hamster ovary (CHO) cells on immobilized fibrinogen.The current study further utilized knock-in mice bearing the β3<sup>E726Q</sup> mutation to explore the underlying mechanisms whereby the E<sup>726</sup> residue differentially influences platelet spreading and clot retraction.Compared to wild type (WT) platelets, β3<sup>E726Q</sup> platelets displayed similar level of β3 expression but partially impaired fibrinogen binding associated with attenuated responses in platelet aggregation and P-selectin exposure. Notably, β3<sup>E726Q</sup> mutation resulted in defective platelet spreading but accelerated clot retraction concomitant with increased clot density. Functionally, β3<sup>E726Q</sup> mice displayed prolonged bleeding time and defective thrombogenesis in vitro and in vivo. Further mechanistic study showed that in β3<sup>E726Q</sup> platelets the activities of RhoA and Rac1 were significantly enhanced following thrombin stimulation, possibly due to reduced binding of Gα13 to the β3 cytoplasmic tail.Taken together, the β3E<sup>726</sup> is a potential novel regulatory site that influences the direct interaction of β3 cytoplasmic tail with Gα13 and therefore the activity of downstream RhoA, a molecular switch that shifts platelet spreading into clot retraction.

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Publication Details

Journal
Thrombosis and Haemostasis
Published
2025-07-24
DOI
https://doi.org/10.1055/a-2664-7955
Citations
2
Primary Topic
Cell Adhesion Molecules Research
Type
article
Field-Weighted Citation Impact
3.24

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article

Integrin β3E726 Regulates the Switch Between Platelet Spreading and Clot Retraction by Interfering Gα13/RhoA Pathway

Shuai Chen, Jie Peng, Ruonan Shao, Han Yan et al.
2 citations
Thrombosis and Haemostasis
Cell Adhesion Molecules Research
3.24
article

Integrin β3E726 Regulates the Switch Between Platelet Spreading and Clot Retraction by Interfering Gα13/RhoA Pathway

Shuai Chen, Jie Peng, Ruonan Shao, Han Yan, Xiaofeng Shi, Jinan Liu, Xiaodong Xi, Honglei Xin, Chao Fang, Jiansong Huang, Rong Huang, Yun Wang, Tiantian Li, Zijian Li, Yichen Liu, Yifei Ma, Yilin Zhu, Bing Xiao, Z.G. Gan, Jiao Wu, Di Yang
article en
2 citations

Abstract

Platelet spreading and clot retraction, albeit both mediated by integrin outside-in signaling, lead to platelet shape changes in two opposite directions. The mechanisms by which these processes are regulated are not fully understood. Our previous study found that E726Q mutation in β3 integrin caused impaired spreading in Chinese hamster ovary (CHO) cells on immobilized fibrinogen.The current study further utilized knock-in mice bearing the β3<sup>E726Q</sup> mutation to explore the underlying mechanisms whereby the E<sup>726</sup> residue differentially influences platelet spreading and clot retraction.Compared to wild type (WT) platelets, β3<sup>E726Q</sup> platelets displayed similar level of β3 expression but partially impaired fibrinogen binding associated with attenuated responses in platelet aggregation and P-selectin exposure. Notably, β3<sup>E726Q</sup> mutation resulted in defective platelet spreading but accelerated clot retraction concomitant with increased clot density. Functionally, β3<sup>E726Q</sup> mice displayed prolonged bleeding time and defective thrombogenesis in vitro and in vivo. Further mechanistic study showed that in β3<sup>E726Q</sup> platelets the activities of RhoA and Rac1 were significantly enhanced following thrombin stimulation, possibly due to reduced binding of Gα13 to the β3 cytoplasmic tail.Taken together, the β3E<sup>726</sup> is a potential novel regulatory site that influences the direct interaction of β3 cytoplasmic tail with Gα13 and therefore the activity of downstream RhoA, a molecular switch that shifts platelet spreading into clot retraction.

Thrombosis and Haemostasis
Guiyang College of Traditional Chinese Medicine (CN), Jiangsu University (CN), Second Military Medical University (CN), Guizhou University (CN), Shanghai Jiao Tong University (CN), XinHua Hospital (CN), Ruijin Hospital (CN), Soochow University (CN), Affiliated Hospital of Jiangsu University (CN), Second Affiliated Hospital of Nanjing Medical University (CN), Shanghai Institute of Hematology (CN), Shanghai Pudong New Area Gongli Hospital (CN), First Affiliated Hospital of Soochow University (CN), First Affiliated Hospital Zhejiang University (CN), Huazhong University of Science and Technology (CN)
National Natural Science Foundation of China, Ministry of Science and Technology of the People's Republic of China
Openalex Percentile: Top 9%
Cell Adhesion Molecules Research
3.24
DOISourceOpenAlex
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