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Tyrosine phosphatase SHP-2 mediates C-type lectin receptor-induced activation of the kinase Syk and anti-fungal T H 17 responses

  • Author(s): Deng, Z
  • Ma, S
  • Zhou, H
  • Zang, A
  • Fang, Y
  • Li, T
  • Shi, H
  • Liu, M
  • Du, M
  • Taylor, PR
  • Zhu, HH
  • Chen, J
  • Meng, G
  • Li, F
  • Chen, C
  • Zhang, Y
  • Jia, XM
  • Lin, X
  • Zhang, X
  • Pearlman, E
  • Li, X
  • Feng, GS
  • Xiao, H
  • et al.

Published Web Location

https://doi.org/10.1038/ni.3155Creative Commons Attribution 4.0 International Public 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 FcRI 3, 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 T H 17 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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