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Tyrosine phosphatase SHP-2 mediates C-type lectin receptor-induced activation of the kinase Syk and anti-fungal TH17 responses.

  • Author(s): Deng, Zihou;
  • Ma, Shixin;
  • Zhou, Hao;
  • Zang, Aiping;
  • Fang, Yiyuan;
  • Li, Tiantian;
  • Shi, Huanjing;
  • Liu, Mei;
  • Du, Min;
  • Taylor, Patricia R;
  • Zhu, Helen He;
  • Chen, Jiangye;
  • Meng, Guangxun;
  • Li, Fubin;
  • Chen, Changbin;
  • Zhang, Yan;
  • Jia, Xin-Ming;
  • Lin, Xin;
  • Zhang, Xiaoming;
  • Pearlman, Eric;
  • Li, Xiaoxia;
  • Feng, Gen-Sheng;
  • Xiao, Hui
  • et al.

Published Web Location

https://doi.org/10.1038/ni.3155Creative Commons 'BY' version 4.0 license
Abstract

Fungal infection stimulates the canonical C-type lectin receptor (CLR) signaling pathway via activation of the tyrosine kinase Syk. Here we identify a crucial role for the tyrosine phosphatase SHP-2 in mediating CLR-induced activation of Syk. Ablation of the gene encoding SHP-2 (Ptpn11; called 'Shp-2' here) in dendritic cells (DCs) and macrophages impaired Syk-mediated signaling and abrogated the expression of genes encoding pro-inflammatory molecules following fungal stimulation. Mechanistically, SHP-2 operated as a scaffold, facilitating the recruitment of Syk to the CLR dectin-1 or the adaptor FcRγ, through its N-SH2 domain and a previously unrecognized carboxy-terminal immunoreceptor tyrosine-based activation motif (ITAM). We found that DC-derived SHP-2 was crucial for the induction of interleukin 1β (IL-1β), IL-6 and IL-23 and anti-fungal responses of the TH17 subset of helper T cells in controlling infection with Candida albicans. Together our data reveal a mechanism by which SHP-2 mediates the activation of Syk in response to fungal infection.

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