| RRC ID |
63160
|
| 著者 |
Zhou F, Elzi DJ, Jayabal P, Ma X, Chiu YC, Chen Y, Blackman B, Weintraub ST, Houghton PJ, Shiio Y.
|
| タイトル |
GDF6-CD99 Signaling Regulates Src and Ewing Sarcoma Growth.
|
| ジャーナル |
Cell Rep
|
| 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.
|
| 巻・号 |
33(5)
|
| ページ |
108332
|
| 公開日 |
2020-11-3
|
| DOI |
10.1016/j.celrep.2020.108332
|
| PII |
S2211-1247(20)31321-8
|
| PMID |
33147457
|
| PMC |
PMC7688343
|
| MeSH |
12E7 Antigen / metabolism*
Animals
CSK Tyrosine-Protein Kinase / metabolism
Cell Proliferation
Down-Regulation
Gene Expression Regulation, Neoplastic
Growth Differentiation Factor 6 / chemistry
Growth Differentiation Factor 6 / metabolism*
Humans
Klippel-Feil Syndrome / genetics
Mice, SCID
Mutation / genetics
Oncogene Proteins, Fusion / metabolism
Protein Domains
Proteome / metabolism
Proteomics
Proto-Oncogene Protein c-fli-1 / metabolism
RNA-Binding Protein EWS / metabolism
Sarcoma, Ewing / metabolism*
Sarcoma, Ewing / pathology*
Signal Transduction*
Transcription, Genetic
src-Family Kinases / metabolism*
|
| IF |
8.109
|
| リソース情報 |
| ヒト・動物細胞 |
Yamato-SS(RCB3577) |
