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Sulfated syndecan 1 is critical to preventing cellular senescence by modulating fibroblast growth factor receptor

Donghee Kang1,2, Seung Hee Jung1,2, Gun-Hee Lee1,2

  • 1Department of Molecular Medicine, Inha University College of Medicine, Incheon, Korea.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|June 13, 2020
PubMed

Insights

Properly sulfated syndecan 1 (SDC1) prevents cellular senescence by regulating fibroblast growth factor receptor 1 (FGFR1) endocytosis. Its depletion enhances FGFR1 signaling, leading to senescence phenotypes.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cellular senescence is induced by various stimuli.
  • Previous work linked 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2) silencing to cellular senescence via fibroblast growth factor receptor 1 (FGFR1) signaling.
  • The precise mechanism connecting heparan sulfation and senescence was unclear.

Purpose of the Study:

  • To investigate the role of heparan sulfate proteoglycans (HSPGs) in FGFR1 signaling and cellular senescence.
  • To elucidate the molecular link between heparan sulfation and senescence.

Main Methods:

  • Depletion of various HSPGs, including syndecan 1 (SDC1).
  • Analysis of FGFR1 internalization and signaling pathways (FGFR1-AKT-p53-p21).
  • Treatment with dynasore to inhibit endocytosis.

Main Results:

  • SDC1 depletion induced senescence phenotypes.
  • Depletion of PAPSS2, SDC1, or heparan sulfate 2-O sulfotransferase 1 (HS2ST1) reduced FGFR1 internalization.
  • Cells showed hyperresponsiveness and prolonged activation of FGFR1-AKT signaling upon FGF2 stimulation.
  • Clathrin- and caveolin-mediated endocytosis contributed to senescence via the FGFR1-AKT-p53-p21 pathway.
  • Dynasore treatment induced senescence, augmented FGFR1-AKT-p53-p21 signaling, and decreased SDC1 expression.
  • Senescent cells exhibited reduced SDC1 expression and FGFR1 internalization, with increased FGFR1-AKT-p53-p21 signaling.

Conclusions:

  • Properly sulfated SDC1 is crucial in preventing cellular senescence.
  • SDC1 regulates senescence by controlling FGFR1 endocytosis.
  • Dysregulation of SDC1 and FGFR1 internalization contributes to senescence.
Keywords:
FGFR1SDC1cellular senescenceendocytosisheparan sulfation

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