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

Fungal infection induces signaling downstream C-type lectin receptors through the activation of the tyrosine kinase Syk. Xiao and colleagues show that the phosphatase SHP-2 recruits Syk to dectin-1. 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 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.