Cell Reports: GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth

Fuchun Zhou (1), David J.Elzi (1, 2), Panneerselvam Jayabal(1), Xiuye Ma(1), Yu-Chiao Chiu (1) Yidong Chen 1,3,4) Barron Blackman(1) Susan T.Weintraub (4, 5) Peter J.Houghton 1,4,6) Yuzuru Shiio (1,4,5,7)

Highlights

  • The autocrine signaling mediated by GDF6 maintains Ewing sarcoma growth
  • The GDF6 prodomain is a ligand for CD99, a widely used marker for Ewing sarcoma
  • GDF6 triggers CSK recruitment to CD99 intracellular domain, inhibiting Src activity
  • Klippel-Feil syndrome-linked GDF6 mutants are hyperactive in CD99-Src signaling

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 suggests the gain-of-function activity for disease-causing GDF6 mutants.

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