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Research article

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
Biochemical Journal Dec 15, 2010, 433 (1) 127-138; DOI: 10.1042/BJ20100589
Chia-Hui Wang
Department of Life Sciences and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
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Fabian Davamani
Department of Life Sciences and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
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Shih-Che Sue
Department of Life Sciences and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, TaiwanInstitute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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Shao-Chen Lee
School of Medicine, Fu Jen Catholic University, Hsinchuang, Taiwan
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Po-long Wu
Department of Physics, National Taiwan Normal University, Taipei, Taiwan
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Fan-Mei Tang
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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Chiaho Shih
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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Tai-huang Huang
Institute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanDepartment of Physics, National Taiwan Normal University, Taipei, Taiwan
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  • For correspondence: bmthh@ibms.sinica.edu.twwgwu@life.nthu.edu.tw
Wen-guey Wu
Department of Life Sciences and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, TaiwanNational Synchrotron Radiation Research Center, Hsinchu, Taiwan
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  • For correspondence: bmthh@ibms.sinica.edu.twwgwu@life.nthu.edu.tw
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Abstract

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 of HATH 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 and membrane 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.

  • cell migration
  • HATH domain
  • heparan sulfate binding
  • hepatoma-derived growth factor (HDGF)
  • macropinocytosis
  • proliferation

Abbreviations: 101-C, peptide encoding Gln101 to the C-terminus of hepatoma-derived growth factor; AF488, Alexa Fluor® 488; CHO, Chinese-hamster ovary; CTB, cholera toxin subunit B; DMEM, Dulbecco's modified Eagle's medium; ERK, extracellular-signal-regulated kinase; FBS, fetal bovine serum; FGF, fibroblast growth factor; GAG, glycosaminoglycan; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HATH, homologous to amino terminus of human hepatoma-derived growth factor; HDGF, hepatoma-derived growth factor; hHDGF, human HDGF; HRP, HDGF-related protein; HS, heparan sulfate; HSPG, HS proteoglycan; MAPK, mitogen-activated protein kinase; MFI, mean fluorescence intensity; MMP, matrix metalloproteinase; PI3K, phosphoinositide 3-kinase; RT, reverse transcription; SPR, surface plasmon resonance; TIMP, tissue inhibitor of MMP

  • © The Authors Journal compilation © 2011 Biochemical Society
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January 2011

Volume: 433 Issue: 1

Biochemical Journal: 433 (1)
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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
Biochemical Journal Jan 2011, 433 (1) 127-138; DOI: 10.1042/BJ20100589
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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
Biochemical Journal Jan 2011, 433 (1) 127-138; DOI: 10.1042/BJ20100589

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Keywords

cell migration
HATH domain
heparan sulfate binding
hepatoma-derived growth factor (HDGF)
macropinocytosis
proliferation

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