@article{4acd4296cffc45bd8da206dce37ecfb3,
title = "GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth",
abstract = "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.",
keywords = "CD99, CSK, Ewing sarcoma, GDF6, Klippel-Feil syndrome, Src, proteomics, secretome",
author = "Fuchun Zhou and Elzi, {David J.} and Panneerselvam Jayabal and Xiuye Ma and Chiu, {Yu Chiao} and Yidong Chen and Barron Blackman and Weintraub, {Susan T.} and Houghton, {Peter J.} and Yuzuru Shiio",
note = "Funding Information: We thank Robert Eisenman for helpful discussions and critical review of the manuscript. We are grateful to Joel Michalek for advice on statistical analyses. We thank the Cooperative Human Tissue Network for Ewing sarcoma tumor RNA samples and the University of Texas Health Science Center at San Antonio (UTHSCSA) Institutional Mass Spectrometry Laboratory (Sammy Pardo ad Dana Molleur) for mass spectrometry analysis. This work was supported by the National Cancer Institute, National Institutes of Health (grant CA202485 to Y.S.; grant CA165995 to P.J.H.; grant K99CA248944 to Y.-C.C.); Cancer Prevention and Research Institute of Texas (grants RP160487, RP160841, and RP190385 to Y.S.; grant RP160716 to P.J.H.; grant RP160732 to Y.C.); Owens Medical Research Foundation (to Y.S.); National Center for Advancing Translational Sciences; National Institutes of Health, through the Clinical and Translational Science Award (CTSA) UL1 TR001120; Mays Cancer Center P30 Cancer Center Support Grant from the National Cancer Institute (CA054174) for the mass spectrometry, the flow cytometry, and the Biostatistics & Bioinformatics shared resources; and National Institutes of Health for purchase of the Orbitrap mass spectrometer (grant 1S10RR025111-01 to S.T.W.). F.Z. D.J.E. and Y.S. designed research; F.Z. D.J.E. P.J. X.M. Y.-C.C. B.B. S.T.W. P.J.H. and Y.S. performed research; F.Z. D.J.E. P.J. Y.C. B.B. S.T.W. P.J.H. and Y.S. analyzed data; and Y.S. wrote the paper with input from other authors. The authors declare no competing interests. Funding Information: We thank Robert Eisenman for helpful discussions and critical review of the manuscript. We are grateful to Joel Michalek for advice on statistical analyses. We thank the Cooperative Human Tissue Network for Ewing sarcoma tumor RNA samples and the University of Texas Health Science Center at San Antonio (UTHSCSA) Institutional Mass Spectrometry Laboratory (Sammy Pardo ad Dana Molleur) for mass spectrometry analysis. This work was supported by the National Cancer Institute , National Institutes of Health (grant CA202485 to Y.S.; grant CA165995 to P.J.H.; grant K99CA248944 to Y.-C.C.); Cancer Prevention and Research Institute of Texas (grants RP160487 , RP160841 , and RP190385 to Y.S.; grant RP160716 to P.J.H.; grant RP160732 to Y.C.); Owens Medical Research Foundation (to Y.S.); National Center for Advancing Translational Sciences ; National Institutes of Health , through the Clinical and Translational Science Award (CTSA) UL1 TR001120 ; Mays Cancer Center P30 Cancer Center Support Grant from the National Cancer Institute ( CA054174 ) for the mass spectrometry, the flow cytometry, and the Biostatistics & Bioinformatics shared resources; and National Institutes of Health for purchase of the Orbitrap mass spectrometer (grant 1S10RR025111-01 to S.T.W.). ",
year = "2020",
month = nov,
day = "3",
doi = "10.1016/j.celrep.2020.108332",
language = "English (US)",
volume = "33",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}