GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth
Summary: 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, n...
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doaj-da3653e6ea5645418c2ab8f61b70d9bb2020-11-25T04:08:37ZengElsevierCell Reports2211-12472020-11-01335108332GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma GrowthFuchun Zhou0David J. Elzi1Panneerselvam Jayabal2Xiuye Ma3Yu-Chiao Chiu4Yidong Chen5Barron Blackman6Susan T. Weintraub7Peter J. Houghton8Yuzuru Shiio9Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USAGreehey 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, USAGreehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USAGreehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USAGreehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USAGreehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Population Health Sciences, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USAGreehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USAMays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229, USAGreehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX 78229, USAGreehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Mays Cancer Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Department of Biochemistry and Structural Biology, The University of Texas Health Science Center, San Antonio, TX 78229, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124720313218GDF6CD99SrcCSKEwing sarcomaKlippel-Feil syndrome |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Fuchun Zhou David J. Elzi Panneerselvam Jayabal Xiuye Ma Yu-Chiao Chiu Yidong Chen Barron Blackman Susan T. Weintraub Peter J. Houghton Yuzuru Shiio |
spellingShingle |
Fuchun Zhou David J. Elzi Panneerselvam Jayabal Xiuye Ma Yu-Chiao Chiu Yidong Chen Barron Blackman Susan T. Weintraub Peter J. Houghton Yuzuru Shiio GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth Cell Reports GDF6 CD99 Src CSK Ewing sarcoma Klippel-Feil syndrome |
author_facet |
Fuchun Zhou David J. Elzi Panneerselvam Jayabal Xiuye Ma Yu-Chiao Chiu Yidong Chen Barron Blackman Susan T. Weintraub Peter J. Houghton Yuzuru Shiio |
author_sort |
Fuchun Zhou |
title |
GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth |
title_short |
GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth |
title_full |
GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth |
title_fullStr |
GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth |
title_full_unstemmed |
GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth |
title_sort |
gdf6-cd99 signaling regulates src and ewing sarcoma growth |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2020-11-01 |
description |
Summary: 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. |
topic |
GDF6 CD99 Src CSK Ewing sarcoma Klippel-Feil syndrome |
url |
http://www.sciencedirect.com/science/article/pii/S2211124720313218 |
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