Syndecan-2 cytoplasmic domain up-regulates matrix metalloproteinase-7 expression via the protein kinase Cγ–mediated FAK/ERK signaling pathway in colon cancer

Bohee Jang, Hyejung Jung, Sojoong Choi, Young Hun Lee, Seung-Taek Lee, Eok Soo Oh

Research output: Contribution to journalArticle

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Abstract

The syndecan family of heparan sulfate proteoglycans contributes to cell adhesion and communication by serving as co-receptors for cell signaling and extracellular matrix molecules. Syndecan-2 is located at the cell surface, and we previously reported that it induces matrix metalloproteinase-7 (MMP-7) expression in colon cancer cells. However, the underlying regulatory mechanisms are unknown. Here, we report that overexpression of syndecan-2 in HT-29 colon cancer cells increases the phosphorylation of focal adhesion kinase (FAK) and ERK in parallel with up-regulated MMP-7 expression, but a syndecan-2 mutant lacking the cytoplasmic domain showed significant reductions in these effects. Consistent with this observation, FAK inhibition via FAK-related non-kinase expression or inhibition of ERK with the ERK1/2 inhibitor SCH772984 diminished the syndecan-2–mediated up-regulation of MMP-7. Activation of PKC enhanced syndecan-2–mediated MMP-7 expression, whereas inhibition of PKC had the opposite effect. Of note, the exogenous expression of syndecan-2 triggered localization of PKC to the membrane. Expression of syndecan-2 harboring a phosphomimetic (S198E) mutation of the variable region of the cytoplasmic domain enhanced MMP-7 expression and FAK phosphorylation. Finally, experimental suppression of shedding of the syndecan-2 extracellular domain did not significantly affect the syndecan-2–mediated up-regulation of MMP-7 in the early period after syndecan-2 overexpression. Taken together, these findings suggest that syndecan-2’s cytoplasmic domain up-regulates MMP-7 expression in colon cancer cells via PKC-mediated activation of FAK/ERK signaling.

Original languageEnglish
Pages (from-to)16321-16332
Number of pages12
JournalJournal of Biological Chemistry
Volume292
Issue number39
DOIs
Publication statusPublished - 2017 Jan 1

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Syndecan-2
Matrix Metalloproteinase 7
Focal Adhesion Protein-Tyrosine Kinases
MAP Kinase Signaling System
Syndecans
Colonic Neoplasms
Protein Kinases
Up-Regulation
Phosphorylation
Cells
Chemical activation
Cell signaling
Heparan Sulfate Proteoglycans
Cell adhesion
Cell Adhesion
Cell Communication
Extracellular Matrix
Membranes
Mutation
Molecules

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

@article{dddb63570af84e6abddfd4f5f153e454,
title = "Syndecan-2 cytoplasmic domain up-regulates matrix metalloproteinase-7 expression via the protein kinase Cγ–mediated FAK/ERK signaling pathway in colon cancer",
abstract = "The syndecan family of heparan sulfate proteoglycans contributes to cell adhesion and communication by serving as co-receptors for cell signaling and extracellular matrix molecules. Syndecan-2 is located at the cell surface, and we previously reported that it induces matrix metalloproteinase-7 (MMP-7) expression in colon cancer cells. However, the underlying regulatory mechanisms are unknown. Here, we report that overexpression of syndecan-2 in HT-29 colon cancer cells increases the phosphorylation of focal adhesion kinase (FAK) and ERK in parallel with up-regulated MMP-7 expression, but a syndecan-2 mutant lacking the cytoplasmic domain showed significant reductions in these effects. Consistent with this observation, FAK inhibition via FAK-related non-kinase expression or inhibition of ERK with the ERK1/2 inhibitor SCH772984 diminished the syndecan-2–mediated up-regulation of MMP-7. Activation of PKC enhanced syndecan-2–mediated MMP-7 expression, whereas inhibition of PKC had the opposite effect. Of note, the exogenous expression of syndecan-2 triggered localization of PKC to the membrane. Expression of syndecan-2 harboring a phosphomimetic (S198E) mutation of the variable region of the cytoplasmic domain enhanced MMP-7 expression and FAK phosphorylation. Finally, experimental suppression of shedding of the syndecan-2 extracellular domain did not significantly affect the syndecan-2–mediated up-regulation of MMP-7 in the early period after syndecan-2 overexpression. Taken together, these findings suggest that syndecan-2’s cytoplasmic domain up-regulates MMP-7 expression in colon cancer cells via PKC-mediated activation of FAK/ERK signaling.",
author = "Bohee Jang and Hyejung Jung and Sojoong Choi and Lee, {Young Hun} and Seung-Taek Lee and Oh, {Eok Soo}",
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Syndecan-2 cytoplasmic domain up-regulates matrix metalloproteinase-7 expression via the protein kinase Cγ–mediated FAK/ERK signaling pathway in colon cancer. / Jang, Bohee; Jung, Hyejung; Choi, Sojoong; Lee, Young Hun; Lee, Seung-Taek; Oh, Eok Soo.

In: Journal of Biological Chemistry, Vol. 292, No. 39, 01.01.2017, p. 16321-16332.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Jung, Hyejung

AU - Choi, Sojoong

AU - Lee, Young Hun

AU - Lee, Seung-Taek

AU - Oh, Eok Soo

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N2 - The syndecan family of heparan sulfate proteoglycans contributes to cell adhesion and communication by serving as co-receptors for cell signaling and extracellular matrix molecules. Syndecan-2 is located at the cell surface, and we previously reported that it induces matrix metalloproteinase-7 (MMP-7) expression in colon cancer cells. However, the underlying regulatory mechanisms are unknown. Here, we report that overexpression of syndecan-2 in HT-29 colon cancer cells increases the phosphorylation of focal adhesion kinase (FAK) and ERK in parallel with up-regulated MMP-7 expression, but a syndecan-2 mutant lacking the cytoplasmic domain showed significant reductions in these effects. Consistent with this observation, FAK inhibition via FAK-related non-kinase expression or inhibition of ERK with the ERK1/2 inhibitor SCH772984 diminished the syndecan-2–mediated up-regulation of MMP-7. Activation of PKC enhanced syndecan-2–mediated MMP-7 expression, whereas inhibition of PKC had the opposite effect. Of note, the exogenous expression of syndecan-2 triggered localization of PKC to the membrane. Expression of syndecan-2 harboring a phosphomimetic (S198E) mutation of the variable region of the cytoplasmic domain enhanced MMP-7 expression and FAK phosphorylation. Finally, experimental suppression of shedding of the syndecan-2 extracellular domain did not significantly affect the syndecan-2–mediated up-regulation of MMP-7 in the early period after syndecan-2 overexpression. Taken together, these findings suggest that syndecan-2’s cytoplasmic domain up-regulates MMP-7 expression in colon cancer cells via PKC-mediated activation of FAK/ERK signaling.

AB - The syndecan family of heparan sulfate proteoglycans contributes to cell adhesion and communication by serving as co-receptors for cell signaling and extracellular matrix molecules. Syndecan-2 is located at the cell surface, and we previously reported that it induces matrix metalloproteinase-7 (MMP-7) expression in colon cancer cells. However, the underlying regulatory mechanisms are unknown. Here, we report that overexpression of syndecan-2 in HT-29 colon cancer cells increases the phosphorylation of focal adhesion kinase (FAK) and ERK in parallel with up-regulated MMP-7 expression, but a syndecan-2 mutant lacking the cytoplasmic domain showed significant reductions in these effects. Consistent with this observation, FAK inhibition via FAK-related non-kinase expression or inhibition of ERK with the ERK1/2 inhibitor SCH772984 diminished the syndecan-2–mediated up-regulation of MMP-7. Activation of PKC enhanced syndecan-2–mediated MMP-7 expression, whereas inhibition of PKC had the opposite effect. Of note, the exogenous expression of syndecan-2 triggered localization of PKC to the membrane. Expression of syndecan-2 harboring a phosphomimetic (S198E) mutation of the variable region of the cytoplasmic domain enhanced MMP-7 expression and FAK phosphorylation. Finally, experimental suppression of shedding of the syndecan-2 extracellular domain did not significantly affect the syndecan-2–mediated up-regulation of MMP-7 in the early period after syndecan-2 overexpression. Taken together, these findings suggest that syndecan-2’s cytoplasmic domain up-regulates MMP-7 expression in colon cancer cells via PKC-mediated activation of FAK/ERK signaling.

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