Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK

Jun Seo Oh, Bong Wan Seo, Tere Diaz, Beiyang Wei, Yvona Ward, Jill M. Ray, Yoko Morioka, Shuliang Shi, Hitoshi Kitayama, Chiaki Takahashi, Makoto Noda, William G. Sletler-Stevenson

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

The antiangiogenic function of the tissue inhibitors of metalloproteinases (TIMPs) has been attributed to their matrix metalloproteinase inhibitory activity. Here we demonstrate that TIMP-1 but not Ala+TIMP-1 inhibits both basal and vascular endothelial growth factor (VEGF)-stimulated migration of human microvascular endothelial cells (hMVECs), suggesting that this effect is dependent on direct inhibition of matrix metalloproteinase (MMP) activity. In contrast, TIMP-2 and mutant Ala+TIMP-2, which is devoid of MMP inhibitory activity, block hMVEC migration in response to VEGF-A stimulation. TIMP-2 and Ala+TIMP-2 also suppress basal hMVEC migration via a time-dependent mechanism mediated by enhanced expression of RECK, a membrane-anchored MMP inhibitor, which, in turn, inhibits cell migration. TIMP-2 treatment of hMVECs increases the association of Crk with C3G, resulting in enhanced Rap1 activation. hMVECs stably expressing Rap1 have increased RECK expression and display reduced cell migration compared with those expressing inactive Rap1(38N). RECK-null murine embryo fibroblasts fail to demonstrate TIMP-2-mediated decrease in cell migration despite activation of Rap1. TIMP-2-induced RECK decreases cell-associated MMP activity. Anti-RECK antibody increases MMP activity and reverses the TIMP-2-mediated reduction in cell migration. The effects of TIMP-2 on RECK expression and cell migration were confirmed in A2058 melanoma cells. These results suggest that TIMP-2 can inhibit cell migration via several distinct mechanisms. First, TIMP-2 can inhibit cell migration after VEGF stimulation by direct inhibition of MMP activity induced in response to VEGF stimulation. Secondly, TIMP-2 can disrupt VEGF signaling required for initiation of hMVEC migration. Third, TIMP-2 can enhance expression of RECK via Rap1 signaling resulting in an indirect, time-dependent inhibition of endothelial cell migration.

Original languageEnglish
Pages (from-to)9062-9069
Number of pages8
JournalCancer Research
Volume64
Issue number24
DOIs
Publication statusPublished - 2004 Dec 15
Externally publishedYes

Fingerprint

Tissue Inhibitor of Metalloproteinase-2
Cell Movement
Endothelial Cells
Matrix Metalloproteinases
Vascular Endothelial Growth Factor A
Tissue Inhibitor of Metalloproteinase-1
Tissue Inhibitor of Metalloproteinases
Matrix Metalloproteinase Inhibitors
Human Activities
Anti-Idiotypic Antibodies
Melanoma
Embryonic Structures

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK. / Oh, Jun Seo; Seo, Bong Wan; Diaz, Tere; Wei, Beiyang; Ward, Yvona; Ray, Jill M.; Morioka, Yoko; Shi, Shuliang; Kitayama, Hitoshi; Takahashi, Chiaki; Noda, Makoto; Sletler-Stevenson, William G.

In: Cancer Research, Vol. 64, No. 24, 15.12.2004, p. 9062-9069.

Research output: Contribution to journalArticle

Oh, JS, Seo, BW, Diaz, T, Wei, B, Ward, Y, Ray, JM, Morioka, Y, Shi, S, Kitayama, H, Takahashi, C, Noda, M & Sletler-Stevenson, WG 2004, 'Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK', Cancer Research, vol. 64, no. 24, pp. 9062-9069. https://doi.org/10.1158/0008-5472.CAN-04-1981
Oh, Jun Seo ; Seo, Bong Wan ; Diaz, Tere ; Wei, Beiyang ; Ward, Yvona ; Ray, Jill M. ; Morioka, Yoko ; Shi, Shuliang ; Kitayama, Hitoshi ; Takahashi, Chiaki ; Noda, Makoto ; Sletler-Stevenson, William G. / Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK. In: Cancer Research. 2004 ; Vol. 64, No. 24. pp. 9062-9069.
@article{aabd3ee9648349028cc20b56e54a88c0,
title = "Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK",
abstract = "The antiangiogenic function of the tissue inhibitors of metalloproteinases (TIMPs) has been attributed to their matrix metalloproteinase inhibitory activity. Here we demonstrate that TIMP-1 but not Ala+TIMP-1 inhibits both basal and vascular endothelial growth factor (VEGF)-stimulated migration of human microvascular endothelial cells (hMVECs), suggesting that this effect is dependent on direct inhibition of matrix metalloproteinase (MMP) activity. In contrast, TIMP-2 and mutant Ala+TIMP-2, which is devoid of MMP inhibitory activity, block hMVEC migration in response to VEGF-A stimulation. TIMP-2 and Ala+TIMP-2 also suppress basal hMVEC migration via a time-dependent mechanism mediated by enhanced expression of RECK, a membrane-anchored MMP inhibitor, which, in turn, inhibits cell migration. TIMP-2 treatment of hMVECs increases the association of Crk with C3G, resulting in enhanced Rap1 activation. hMVECs stably expressing Rap1 have increased RECK expression and display reduced cell migration compared with those expressing inactive Rap1(38N). RECK-null murine embryo fibroblasts fail to demonstrate TIMP-2-mediated decrease in cell migration despite activation of Rap1. TIMP-2-induced RECK decreases cell-associated MMP activity. Anti-RECK antibody increases MMP activity and reverses the TIMP-2-mediated reduction in cell migration. The effects of TIMP-2 on RECK expression and cell migration were confirmed in A2058 melanoma cells. These results suggest that TIMP-2 can inhibit cell migration via several distinct mechanisms. First, TIMP-2 can inhibit cell migration after VEGF stimulation by direct inhibition of MMP activity induced in response to VEGF stimulation. Secondly, TIMP-2 can disrupt VEGF signaling required for initiation of hMVEC migration. Third, TIMP-2 can enhance expression of RECK via Rap1 signaling resulting in an indirect, time-dependent inhibition of endothelial cell migration.",
author = "Oh, {Jun Seo} and Seo, {Bong Wan} and Tere Diaz and Beiyang Wei and Yvona Ward and Ray, {Jill M.} and Yoko Morioka and Shuliang Shi and Hitoshi Kitayama and Chiaki Takahashi and Makoto Noda and Sletler-Stevenson, {William G.}",
year = "2004",
month = "12",
day = "15",
doi = "10.1158/0008-5472.CAN-04-1981",
language = "English",
volume = "64",
pages = "9062--9069",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "24",

}

TY - JOUR

T1 - Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK

AU - Oh, Jun Seo

AU - Seo, Bong Wan

AU - Diaz, Tere

AU - Wei, Beiyang

AU - Ward, Yvona

AU - Ray, Jill M.

AU - Morioka, Yoko

AU - Shi, Shuliang

AU - Kitayama, Hitoshi

AU - Takahashi, Chiaki

AU - Noda, Makoto

AU - Sletler-Stevenson, William G.

PY - 2004/12/15

Y1 - 2004/12/15

N2 - The antiangiogenic function of the tissue inhibitors of metalloproteinases (TIMPs) has been attributed to their matrix metalloproteinase inhibitory activity. Here we demonstrate that TIMP-1 but not Ala+TIMP-1 inhibits both basal and vascular endothelial growth factor (VEGF)-stimulated migration of human microvascular endothelial cells (hMVECs), suggesting that this effect is dependent on direct inhibition of matrix metalloproteinase (MMP) activity. In contrast, TIMP-2 and mutant Ala+TIMP-2, which is devoid of MMP inhibitory activity, block hMVEC migration in response to VEGF-A stimulation. TIMP-2 and Ala+TIMP-2 also suppress basal hMVEC migration via a time-dependent mechanism mediated by enhanced expression of RECK, a membrane-anchored MMP inhibitor, which, in turn, inhibits cell migration. TIMP-2 treatment of hMVECs increases the association of Crk with C3G, resulting in enhanced Rap1 activation. hMVECs stably expressing Rap1 have increased RECK expression and display reduced cell migration compared with those expressing inactive Rap1(38N). RECK-null murine embryo fibroblasts fail to demonstrate TIMP-2-mediated decrease in cell migration despite activation of Rap1. TIMP-2-induced RECK decreases cell-associated MMP activity. Anti-RECK antibody increases MMP activity and reverses the TIMP-2-mediated reduction in cell migration. The effects of TIMP-2 on RECK expression and cell migration were confirmed in A2058 melanoma cells. These results suggest that TIMP-2 can inhibit cell migration via several distinct mechanisms. First, TIMP-2 can inhibit cell migration after VEGF stimulation by direct inhibition of MMP activity induced in response to VEGF stimulation. Secondly, TIMP-2 can disrupt VEGF signaling required for initiation of hMVEC migration. Third, TIMP-2 can enhance expression of RECK via Rap1 signaling resulting in an indirect, time-dependent inhibition of endothelial cell migration.

AB - The antiangiogenic function of the tissue inhibitors of metalloproteinases (TIMPs) has been attributed to their matrix metalloproteinase inhibitory activity. Here we demonstrate that TIMP-1 but not Ala+TIMP-1 inhibits both basal and vascular endothelial growth factor (VEGF)-stimulated migration of human microvascular endothelial cells (hMVECs), suggesting that this effect is dependent on direct inhibition of matrix metalloproteinase (MMP) activity. In contrast, TIMP-2 and mutant Ala+TIMP-2, which is devoid of MMP inhibitory activity, block hMVEC migration in response to VEGF-A stimulation. TIMP-2 and Ala+TIMP-2 also suppress basal hMVEC migration via a time-dependent mechanism mediated by enhanced expression of RECK, a membrane-anchored MMP inhibitor, which, in turn, inhibits cell migration. TIMP-2 treatment of hMVECs increases the association of Crk with C3G, resulting in enhanced Rap1 activation. hMVECs stably expressing Rap1 have increased RECK expression and display reduced cell migration compared with those expressing inactive Rap1(38N). RECK-null murine embryo fibroblasts fail to demonstrate TIMP-2-mediated decrease in cell migration despite activation of Rap1. TIMP-2-induced RECK decreases cell-associated MMP activity. Anti-RECK antibody increases MMP activity and reverses the TIMP-2-mediated reduction in cell migration. The effects of TIMP-2 on RECK expression and cell migration were confirmed in A2058 melanoma cells. These results suggest that TIMP-2 can inhibit cell migration via several distinct mechanisms. First, TIMP-2 can inhibit cell migration after VEGF stimulation by direct inhibition of MMP activity induced in response to VEGF stimulation. Secondly, TIMP-2 can disrupt VEGF signaling required for initiation of hMVEC migration. Third, TIMP-2 can enhance expression of RECK via Rap1 signaling resulting in an indirect, time-dependent inhibition of endothelial cell migration.

UR - http://www.scopus.com/inward/record.url?scp=10844219880&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10844219880&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-04-1981

DO - 10.1158/0008-5472.CAN-04-1981

M3 - Article

VL - 64

SP - 9062

EP - 9069

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 24

ER -