Cell surface heparan sulfates mediate internalization of the PWWP/HATH domain of HDGF via macropinocytosis to fine-tune cell signalling processes involved in fibroblast cell migration

Chia Hui Wang, Fabian Davamani, Shih Che Sue, Shao Chen Lee, Po Long Wu, Fan Mei Tang, Chiaho Shih, Tai Huang Huang, Wen Guey Wu

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24 Citations (Scopus)


HDGF (hepatoma-derived growth factor) stimulates cell proliferation by functioning on both sides of the plasma membrane as a ligand for membrane receptor binding to trigger cell signalling and as a stimulator for DNA synthesis in the nucleus. Although HDGF was initially identified as a secretory heparin-binding protein, the biological significance of its heparin-binding ability remains to be determined. In the present study we demonstrate that cells devoid of surface HS (heparan sulfate) were unable to internalize HDGF, HATH (N-terminal domain of HDGF consisting of amino acid residues 1-100, including the PWWP motif) and HATH(K96A) (single-site mutant form of HATH devoid of receptor binding activity), suggesting that the binding ofHATH to surface HS is important for HDGF internalization. We further demonstrate that both HATH and HATH(K96A) could be internalized through macropinocytosis after binding to the cell surface HS. Interestingly, HS-mediated HATH(K96A) internalization is found to exhibit an inhibitory effect on cell migration and proliferation in contrast with that observed for HATH action on NIH 3T3 cells, suggesting that HDGF exploits the innate properties of both cell surface HS andmembrane receptor via the HATH domain to affect related cell signalling processes. The present study indicates that MAPK (mitogen-activated protein kinase) signalling pathways could be affected by the HS-mediated HATH internalization to regulate cell migration in NIH 3T3 fibroblasts, as judged from the differential effect of HATH and HATH(K96A) treatment on the expression level of matrix metalloproteases.

Original languageEnglish
Pages (from-to)127-138
Number of pages12
JournalBiochemical Journal
Issue number1
Publication statusPublished - 2011 Jan 1



  • Cell migration
  • HATH domain
  • Heparan sulfate binding
  • Hepatoma-derived growth factor (HDGF)
  • Macropinocytosis
  • Proliferation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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