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’.

效应淋巴细胞，包括 NK 和 T 细胞，表达 FasL。Fas 是肿瘤细胞中 FasL 的受体，其表达使它们对 NK 和 T 细胞介导的杀伤作用敏感。FasL 在启动肿瘤细胞死亡信号中的功能相关性已得到充分表征。然而，FasL 下游的细胞质相互作用伙伴和潜在的信号通路远未完全确定。FasL 具有 81 个氨基酸长的细胞质尾部，具有多个独特的募集基序。我们预测多个相互依赖的信号复合体形成了 FasL 下游“反向信号”的核心。FasL 富含脯氨酸结构域与 PI(3)K-p85α 的 SH3 结构域之间的直接相互作用启动了第一个途径。这种级联帮助 FasL 通过 PIP ₃链接到 PLC-γ2或 mTOR 复合物的 Akt 依赖性激活。独立地，FasL 的 GRB2/GADs 结合 PXXP 细胞质基序可以启动 Ras-GTP 依赖性 PAK1→C-Raf→MEK1/2→ERK1/2 激活。FasL 可以通过富含脯氨酸的域招募 Fyn，从而招募 ADAP。通过其直接与 Carma1 和 TAK1 相互作用的能力，ADAP 启动了基于 Carma1/Bcl10/Malt1 的 CBM 信号小体的形成，该信号小体主要负责炎性细胞因子的产生。在这里，我们探索 FasL 的保守细胞质结构域、相互作用的潜在信号分子以及效应淋巴细胞内的功能性下游后果，以定义 FasL 介导的“反向信号”。