Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA.
Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA; BioAffinity Technologies, Inc., 1 UTSA Circle, San Antonio, TX 78249, USA.
Cell Rep. 2020 Nov 3;33(5):108332. doi: 10.1016/j.celrep.2020.108332.
We report here that the autocrine signaling mediated by growth and differentiation factor 6 (GDF6), a member of the bone morphogenetic protein (BMP) family of cytokines, maintains Ewing sarcoma growth by preventing Src hyperactivation. Surprisingly, Ewing sarcoma depends on the prodomain, not the BMP domain, of GDF6. We demonstrate that the GDF6 prodomain is a ligand for CD99, a transmembrane protein that has been widely used as a marker of Ewing sarcoma. The binding of the GDF6 prodomain to the CD99 extracellular domain results in recruitment of CSK (C-terminal Src kinase) to the YQKKK motif in the intracellular domain of CD99, inhibiting Src activity. GDF6 silencing causes hyperactivation of Src and p21-dependent growth arrest. We demonstrate that two GDF6 prodomain mutants linked to Klippel-Feil syndrome are hyperactive in CD99-Src signaling. These results reveal a cytokine signaling pathway that regulates the CSK-Src axis and cancer cell proliferation and suggest the gain-of-function activity for disease-causing GDF6 mutants.
我们在此报告，由生长分化因子 6（GDF6）介导的自分泌信号通过防止Src 过度激活来维持尤文肉瘤的生长。令人惊讶的是，尤文肉瘤依赖于 GDF6 的前肽，而不是 BMP 结构域。我们证明 GDF6 前肽是 CD99 的配体，CD99 是一种跨膜蛋白，被广泛用作尤文肉瘤的标志物。GDF6 前肽与 CD99 细胞外结构域的结合导致 CSK（C 末端Src 激酶）募集到 CD99 细胞内结构域中的 YQKKK 基序，从而抑制 Src 活性。GDF6 沉默导致 Src 过度激活和 p21 依赖性生长停滞。我们证明与克莱佩尔-费尔综合征相关的两种 GDF6 前肽突变体在 CD99-Src 信号传导中具有高活性。这些结果揭示了一种细胞因子信号通路，该通路调节 CSK-Src 轴和癌细胞增殖，并提示致病 GDF6 突变体的功能获得活性。
