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Tyrosine phosphatase Shp2 regulates p115RhoGEF/Rho-dependent dendritic cell migration

Cellular & Molecular Immunology volume 18, pages 755–757 (2021)Cite this article

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The orchestrated migration of dendritic cells (DCs) to secondary lymphoid organs relies on C-C chemokine receptor type 7 (CCR7) and its ligand C-C motif chemokine ligand 19 (CCL19), and DC migration to lymph nodes is crucial for the initiation and progression of adaptive immune responses.1 The establishment and maintenance of cell polarity are controlled by Rho guanosine triphosphatases (GTPases), including Rho, Rac, and cell division control protein 42, which mediate the switch between inactive GDP-bound and active GTP-bound protein states to regulate cell cytoskeletal rearrangement and cell migration. This GDP–GTP cycle is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs are responsible for the activation of Rho by catalyzing the exchange of bound GDP to GTP, while GAPs increase Rho-GTP hydration to inactivate Rho. These two types of proteins are regulated by phosphorylation modifications and together mediate Rho activation.2,3 Shp2, a ubiquitously expressed tyrosine phosphatase, contains two Src homology 2 (SH2) domains and one catalytic protein tyrosine phosphatase (PTP) domain. Shp2 mediates multiple signaling events across a variety of cellular functions by dephosphorylating specific proteins involved in the corresponding physiological and pathological processes.4,5 However, the mechanism of DC migration regulated by Shp2 and Rho-GTP remains unclear. In our study, we demonstrated that Shp2 deficiency inhibited bone marrow-derived DC (BMDC) migration both in vitro and in vivo. Further analysis showed that the absence of Shp2 in lipopolysaccharide (LPS)-stimulated BMDCs increased the phosphorylation of p115RhoGEF and augmented the activity of Rho-GTP. Increased Rho-GTP activity promoted the phosphorylation of myosin light chain (MLC), cofilin, and Pyk2, resulting in impaired DC migration.

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Acknowledgements

We thank Dr Gen-Sheng Feng (University of California, USA) for the Shp2f/f mice and Dr Shumin Duan (Zhejiang University, China) for the OT-II TCR transgenic mice. This work was supported by the National Nature Science Foundation of China (81700022, 81873418, and 31870901) and the Zhejiang Provincial Natural Science Foundation (LY18H010001).

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  1. These authors contributed equally: Yun Xu, Yun Zhang

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  1. Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China

    Yun Xu, Yanyan Yang, Yanqi Liu, Qiaoying Tian, Pan Liu, Zhifan Ding, Hongqiang Cheng, Xue Zhang & Yuehai Ke

  2. Institute of Basic Research in Clinical Medicine, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, China

    Yun Zhang

  3. Department of Pathology and Pathophysiology and Department of Respiratory Medicine at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China

    Xue Zhang & Yuehai Ke

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  1. Yun Xu
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Xu, Y., Zhang, Y., Yang, Y. et al. Tyrosine phosphatase Shp2 regulates p115RhoGEF/Rho-dependent dendritic cell migration. Cell Mol Immunol 18, 755–757 (2021). https://doi.org/10.1038/s41423-020-0414-y

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