Novel PI(3)K-p85/p1108-ITK-LAT-PLC-2 and Fyn-ADAP-Carma1-TAK1 Pathways Define Reverse Signaling via FasL

The role of FasL in initiating death signals through Fas is well characterized. However, the reverse signaling pathway downstream of FasL in effector lymphocytes is poorly understood. Here, we identify that FasL functions as an independent activation receptor in NK cells. Activation via FasL results in the production of IFN-gamma, GM-CSF, RANTES, MIP-1 alpha, and MIP1-13. Proximal signaling of FasL requires Lck and Fyn. Upon activation, FasL facilitates the phosphorylation of PI(3)K-p85 alpha/p55 alpha subunits. A catalytically inactive PI(3)K-p110 delta D910A mutation significantly impairs the cytokine and chemokine production by FasL. Activation of ITK and LAT downstream of FasL plays a central role in recruiting and phosphorylating PLC-gamma 2. Importantly, Fyn-mediated recruitment of ADAP links FasL to the Carma1/ Bcl10/Tak1 signalosome. Lack of Carma1, CARD domain of Carma1, or Tak1 significantly reduces FasL-mediated cytokine and chemokine production. These findings, for the first time, provide a detailed molecular blueprint that defines FasL-mediated reverse signaling.