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

Cellular senescence can be triggered by various intrinsic and extrinsic stimuli. We previously reported that silencing of 3′‐phosphoadenosine 5′‐phosphosulfate synthetase 2 (PAPSS2) induces cellular senescence through augmented fibroblast growth factor receptor 1 (FGFR1) signaling. However, the exac...

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Veröffentlicht in:The FASEB journal 2020-08, Vol.34 (8), p.10316-10328
Hauptverfasser: Kang, Donghee, Jung, Seung Hee, Lee, Gun‐Hee, Lee, Seongju, Park, Heon Joo, Ko, Young‐Gyu, Kim, Yong‐Nyun, Lee, Jae‐Seon
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container_end_page 10328
container_issue 8
container_start_page 10316
container_title The FASEB journal
container_volume 34
creator Kang, Donghee
Jung, Seung Hee
Lee, Gun‐Hee
Lee, Seongju
Park, Heon Joo
Ko, Young‐Gyu
Kim, Yong‐Nyun
Lee, Jae‐Seon
description Cellular senescence can be triggered by various intrinsic and extrinsic stimuli. We previously reported that silencing of 3′‐phosphoadenosine 5′‐phosphosulfate synthetase 2 (PAPSS2) induces cellular senescence through augmented fibroblast growth factor receptor 1 (FGFR1) signaling. However, the exact molecular mechanism connecting heparan sulfation and cellular senescence remains unclear. Here, we investigated the potential involvement of heparan sulfate proteoglycans (HSPGs) in augmented FGFR1 signaling and cellular senescence. Depletion of several types of HSPGs revealed that cells depleted of syndecan 1 (SDC1) exhibited typical senescence phenotypes, and those depleted of PAPSS2‐, SDC1‐, or heparan sulfate 2‐O sulfotransferase 1 (HS2ST1) showed decreased FGFR1 internalization along with hyperresponsiveness to and prolonged activation of fibroblast growth factor 2 (FGF2)‐stimulated FGFR1‐ v‐akt murine thymoma viral oncogene homolog (AKT) signaling. Clathrin‐ and caveolin‐mediated FGFR1 endocytosis contributed to cellular senescence through the FGFR1‐AKT‐p53‐p21 signaling pathway. Dynasore treatment triggered senescence phenotypes, augmented FGFR1‐AKT‐p53‐p21 signaling, and decreased SDC1 expression. Finally, the replicatively and prematurely senescent cells were characterized by decreases of SDC1 expression and FGFR1 internalization, and an increase in FGFR1‐AKT‐p53‐p21 signaling. Together, our results demonstrate that properly sulfated SDC1 plays a critical role in preventing cellular senescence through the regulation of FGFR1 endocytosis.
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We previously reported that silencing of 3′‐phosphoadenosine 5′‐phosphosulfate synthetase 2 (PAPSS2) induces cellular senescence through augmented fibroblast growth factor receptor 1 (FGFR1) signaling. However, the exact molecular mechanism connecting heparan sulfation and cellular senescence remains unclear. Here, we investigated the potential involvement of heparan sulfate proteoglycans (HSPGs) in augmented FGFR1 signaling and cellular senescence. Depletion of several types of HSPGs revealed that cells depleted of syndecan 1 (SDC1) exhibited typical senescence phenotypes, and those depleted of PAPSS2‐, SDC1‐, or heparan sulfate 2‐O sulfotransferase 1 (HS2ST1) showed decreased FGFR1 internalization along with hyperresponsiveness to and prolonged activation of fibroblast growth factor 2 (FGF2)‐stimulated FGFR1‐ v‐akt murine thymoma viral oncogene homolog (AKT) signaling. Clathrin‐ and caveolin‐mediated FGFR1 endocytosis contributed to cellular senescence through the FGFR1‐AKT‐p53‐p21 signaling pathway. Dynasore treatment triggered senescence phenotypes, augmented FGFR1‐AKT‐p53‐p21 signaling, and decreased SDC1 expression. Finally, the replicatively and prematurely senescent cells were characterized by decreases of SDC1 expression and FGFR1 internalization, and an increase in FGFR1‐AKT‐p53‐p21 signaling. 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We previously reported that silencing of 3′‐phosphoadenosine 5′‐phosphosulfate synthetase 2 (PAPSS2) induces cellular senescence through augmented fibroblast growth factor receptor 1 (FGFR1) signaling. However, the exact molecular mechanism connecting heparan sulfation and cellular senescence remains unclear. Here, we investigated the potential involvement of heparan sulfate proteoglycans (HSPGs) in augmented FGFR1 signaling and cellular senescence. Depletion of several types of HSPGs revealed that cells depleted of syndecan 1 (SDC1) exhibited typical senescence phenotypes, and those depleted of PAPSS2‐, SDC1‐, or heparan sulfate 2‐O sulfotransferase 1 (HS2ST1) showed decreased FGFR1 internalization along with hyperresponsiveness to and prolonged activation of fibroblast growth factor 2 (FGF2)‐stimulated FGFR1‐ v‐akt murine thymoma viral oncogene homolog (AKT) signaling. Clathrin‐ and caveolin‐mediated FGFR1 endocytosis contributed to cellular senescence through the FGFR1‐AKT‐p53‐p21 signaling pathway. Dynasore treatment triggered senescence phenotypes, augmented FGFR1‐AKT‐p53‐p21 signaling, and decreased SDC1 expression. Finally, the replicatively and prematurely senescent cells were characterized by decreases of SDC1 expression and FGFR1 internalization, and an increase in FGFR1‐AKT‐p53‐p21 signaling. 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subjects Caveolins - metabolism
Cell Line
Cell Line, Tumor
cellular senescence
Cellular Senescence - physiology
Clathrin - metabolism
endocytosis
Endocytosis - physiology
FGFR1
Fibroblast Growth Factor 2 - metabolism
heparan sulfation
Heparitin Sulfate - metabolism
Humans
MCF-7 Cells
Receptor, Fibroblast Growth Factor, Type 1 - metabolism
SDC1
Signal Transduction - physiology
Sulfates - metabolism
Syndecan-1 - metabolism
title Sulfated syndecan 1 is critical to preventing cellular senescence by modulating fibroblast growth factor receptor endocytosis
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