Transforming growth factor β1 signaling via interaction with cell surface hyal-2 and recruitment of WWOX/WOX1

Li Jin Hsu, Lori Schultz, Qunying Hong, Kris Van Moer, John Heath, Meng Yen Li, Feng Jie Lai, Sing Ru Lin, Ming Hui Lee, Cheng Peng Lo, Yee Shin Lin, Shur Tzu Chen, Nan Shan Chang*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

69 Citations (Scopus)


Transforming growth factor β (TGF-β) initiates multiple signal pathways and activates many downstream kinases. Here, we determined that TGF-β1 bound cell surface hyaluronidase Hyal-2 on microvilli in type II TGF-β 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-WOX1 complexes for relocation to the nuclei. TGF-β1 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-β1 supports L929 fibroblast growth. In contrast, transiently overexpressed WOX1 and Hyal-2 sensitized L929 to TGF-β1-induced apoptosis. Together, TGF-β1 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.

Original languageEnglish
Pages (from-to)16049-16059
Number of pages11
JournalJournal of Biological Chemistry
Issue number23
Publication statusPublished - 5 Jun 2009
Externally publishedYes


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