The ß1-integrin-dependent function of RECK in physiologic and tumor angiogenesis.
Vascular endothelial cells produce considerable amounts of matrix metalloproteinases (MMP), including MMP-2, MMP-9, and membrane type 1 (MT1)-MMP. However, little is known about the regulatory mechanisms of these protease activities exhibited during vascular development. A glycosylphosphatidylinositol-anchored glycoprotein, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), has been shown to attenuate MMP-2 maturation by directly interacting with MT1-MMP. Here, we show that an angiogenic factor angiopoietin-1 induces RECK expression in human umbilical vein endothelial cells (HUVEC), and RECK depletion in these cells results in defective vascular tube formation and cellular senescence. We further observed that RECK depletion downregulates beta1-integrin activation, which was associated with decreased autophosphorylation of focal adhesion kinase and increased expression of a cyclin-dependent kinase inhibitor p21(CIP1). In agreement, significant downregulation of beta1-integrin activity was observed in vascular endothelial cells in Reck-/- mouse embryos. In HUVECs, specific inhibition of MMP-2 significantly antagonized the effect of RECK depletion on beta1-integrin signaling, cell proliferation, and tube elongation. Furthermore, we observed that hypervascular tumor-derived cell lines can induce high RECK expression in convoluted vascular endothelial cells, and this in turn supports tumor growth. Targeting RECK specifically in tumor-associated vascular endothelial cells resulted in tumor regression. Therefore, we propose that RECK in tumor vascular endothelial cells can be an interesting target of cancer treatment via abortion of tumor angiogenesis.
Miki
Takao
T
Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Japan.
Shamma
Awad
A
Kitajima
Shunsuke
S
Takegami
Yujiro
Y
Noda
Makoto
M
Nakashima
Yasuaki
Y
Watanabe
Ken-Ichiro
K
Takahashi
Chiaki
C
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000235:genetics*; D034622:RNA Interference
D058851:GPI-Linked Proteins; D019012:Integrin beta1; D008562:Membrane Glycoproteins; C115460:RECK protein, human