GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth.
GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth.
复制标题
DOI：
10.1016/j.celrep.2020.108332
复制
发表时间：
2020-11-03
期刊：
影响因子：
8.8
通讯作者：
Shiio Y
中科院分区：
文献类型：
--
作者：
Zhou F;Elzi DJ;Jayabal P;Ma X;Chiu YC;Chen Y;Blackman B;Weintraub ST;Houghton PJ;Shiio Y
我们在这里报告，自分泌信号介导的生长和分化因子6（GDF 6），骨形态发生蛋白（BMP）家族的细胞因子的成员，保持尤文肉瘤的生长，防止Src过度激活。令人惊讶的是，尤文肉瘤依赖于GDF 6的前结构域，而不是BMP结构域。我们证明了GDF 6前结构域是CD 99的配体，CD 99是一种跨膜蛋白，已被广泛用作尤文肉瘤的标志物。GDF 6前结构域与CD 99胞外结构域的结合导致CSK（C-末端Src激酶）募集到CD 99胞内结构域中的YQKKK基序，抑制Src活性。GDF 6沉默导致Src的过度活化和p21依赖性生长停滞。我们证明了与Klippel-Feil综合征相关的两个GDF 6前结构域突变体在CD 99-Src信号传导中过度活跃。这些结果揭示了调节CSK-Src轴和癌细胞增殖的细胞因子信号传导途径，并表明致病GDF 6突变体的功能获得活性。尤因肉瘤是由EWS-ETS融合癌蛋白驱动的，但人们对调节这种癌症的细胞外信号传导知之甚少。Zhou等报道GDF 6的前结构域是CD 99的配体，通过CSK抑制Src并以自分泌方式维持尤文肉瘤生长。
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. Ewing sarcoma is driven by the EWS-ETS fusion oncoprotein, but little is known about the extracellular signaling regulating this cancer. Zhou et al. report that the prodomain of GDF6 is a ligand for CD99, inhibiting Src through CSK and maintaining Ewing sarcoma growth in an autocrine fashion.
登录
查看更多内容
影响因子：
4.8
作者：
Arbet-Engels, C;Tartare-Deckert, S;Eckhart, W
通讯作者：
Eckhart, W
影响因子：
--
作者：
Dasgupta A;Trucco M;Rainusso N;Bernardi RJ;Shuck R;Kurenbekova L;Loeb DM;Yustein JT
通讯作者：
Yustein JT
DOI：
10.1006/bbrc.1995.1712
发表时间：
1995-05-25
影响因子：
3.1
作者：
AONO, A;HAZAMA, M;FUJISAWA, Y
通讯作者：
FUJISAWA, Y
影响因子：
--
作者：
Jayabal, Panneerselvam;Houghton, Peter J;Shiio, Yuzuru
通讯作者：
Shiio, Yuzuru
影响因子：
4.7
作者：
Gonzalez, Iranzu;Vicent, Silvestre;Lecanda, Fernando
通讯作者：
Lecanda, Fernando