Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 23, Pages 16049-16059Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M806688200
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Funding
- American Heart Association
- Department of Defense [DAMD17-03-1-0736, W81XWH-08-1-0682]
- Guthrie Foundation for Education and Research
- National Science Council, Taiwan [NSC96-2320-B-006-014, 96-2628-B-006-041-MY3, 96-2628-B-006-045-MY3]
- National Health Research Institute, Taiwan [NHRI-EX97-9704BI]
- National Cheng Kung University Landmark [C0167, R026]
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Transforming growth factor beta(TGF-beta) initiates multiple signal pathways and activates many downstream kinases. Here, we determined that TGF-beta 1 bound cell surface hyaluronidase Hyal-2 on microvilli in type II TGF-beta receptor-deficient HCT116 cells, as determined by immunoelectron microscopy. This binding resulted in recruitment of proapoptotic WOX1 ( also named WWOX or FOR) and formation of Hyal-2 center dot WOX1 complexes for relocation to the nuclei. TGF-beta 1 strengthened the binding of the catalytic domain of Hyal-2 with the N-terminal Tyr-33-phosphorylated WW domain of WOX1, as determined by time lapse fluorescence resonance energy transfer analysis in live cells, co-immunoprecipitation, and yeast two-hybrid domain/domain mapping. In promoter activation assay, ectopic WOX1 or Hyal-2 alone increased the promoter activity driven by Smad. In combination, WOX1 and Hyal-2 dramatically enhanced the promoter activation (8-9-fold increases), which subsequently led to cell death (> 95% of promoter-activated cells). TGF-beta 1 supports L929 fibroblast growth. In contrast, transiently overexpressed WOX1 and Hyal-2 sensitized L929 to TGF-beta 1-induced apoptosis. Together, TGF-beta 1 invokes a novel signaling by engaging cell surface Hyal-2 and recruiting WOX1 for regulating the activation of Smad-driven promoter, thereby controlling cell growth and death.
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