GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth
Fuchun Zhou,
David J. Elzi,
Panneerselvam Jayabal,
Xiuye Ma,
Yu-Chiao Chiu,
Yidong Chen,
Barron Blackman,
Susan T. Weintraub,
Peter J. Houghton,
Yuzuru Shiio
Affiliations
Fuchun Zhou
Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
David J. Elzi
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
Panneerselvam Jayabal
Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Xiuye Ma
Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Yu-Chiao Chiu
Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Yidong Chen
Greehey 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, USA
Barron Blackman
Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229, USA
Susan T. Weintraub
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
Peter J. Houghton
Greehey 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, USA
Yuzuru Shiio
Greehey 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 author
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.
