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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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