Molecular mechanisms of FasL-mediated ‘reverse-signaling’

Effector lymphocytes, including NK and T cells, express FasL. Expression of Fas, the receptor for FasL in tumor cells, renders them susceptible to NK and T cell-mediated killing. The functional relevance of FasL in initiating death signals in tumor cells is well-characterized. However, the cytoplasmic interacting partners and the potential signaling pathways downstream of FasL are far from fully defined. FasL possesses an 81 amino acid long cytoplasmic tail with multiple unique recruitment motifs. We predict multiple interdependent signaling complexes form the core of the 'reverse signaling' downstream of FasL. A direct interaction between the proline-rich domain of FasL and the SH3 domain of PI(3)K-p85α initiates the first pathway. This cascade helps FasL to link to PLC-γ2 via PIP3 or the Akt-dependent activation of mTOR complexes. Independently, a GRB2/GADs-binding PXXP cytoplasmic motif of FasL can initiate a Ras-GTP-dependent PAK1→C-Raf→MEK1/2→ERK1/2 activation. FasL can recruit Fyn via the proline-rich domain leading to the recruitment of ADAP. Through its ability to directly interact with Carma1 and TAK1, ADAP initiates the formation of the Carma1/Bcl10/Malt1-based CBM signalosome that is primarily responsible for inflammatory cytokine production. Here, we explore the conserved cytoplasmic domains of FasL, the potential signaling molecules that interact, and the functional downstream consequences within the effector lymphocytes to define the FasL-mediated 'reverse signaling'.