title: Integrin α2β1 mediates tyrosine phosphorylation of vascular endothelial cadherin induced by invasive breast cancer cells.
abstract: The molecular mechanisms that regulate the endothelial response during transendothelial migration (TEM) of invasive cancer cells remain elusive. Tyrosine phosphorylation of vascular endothelial cadherin (VE-cad) has been implicated in the disruption of endothelial cell adherens junctions and in the diapedesis of metastatic cancer cells. We sought to determine the signaling mechanisms underlying the disruption of endothelial adherens junctions after the attachment of invasive breast cancer cells. Attachment of invasive breast cancer cells (MDA-MB-231) to human umbilical vein endothelial cells induced tyrosine phosphorylation of VE-cad, dissociation of β-catenin from VE-cad, and retraction of endothelial cells. Breast cancer cell-induced tyrosine phosphorylation of VE-cad was mediated by activation of the H-Ras/Raf/MEK/ERK signaling cascade and depended on the phosphorylation of endothelial myosin light chain (MLC). The inhibition of H-Ras or MLC in endothelial cells inhibited TEM of MDA-MB-231 cells. VE-cad tyrosine phosphorylation in endothelial cells induced by the attachment of MDA-MB-231 cells was mediated by MDA-MB-231 α(2)β(1) integrin. Compared with highly invasive MDA-MB-231 breast cancer cells, weakly invasive MCF-7 breast cancer cells expressed lower levels of α(2)β(1) integrin. TEM of MCF-7 as well as induction of VE-cad tyrosine phosphorylation and dissociation of β-catenin from the VE-cad complex by MCF-7 cells were lower than in MDA-MB-231 cells. These processes were restored when MCF-7 cells were treated with β(1)-activating antibody. Moreover, the response of endothelial cells to the attachment of prostatic (PC-3) and ovarian (SKOV3) invasive cancer cells resembled the response to MDA-MB-231 cells. Our study showed that the MDA-MB-231 cell-induced disruption of endothelial adherens junction integrity is triggered by MDA-MB-231 cell α(2)β(1) integrin and is mediated by H-Ras/MLC-induced tyrosine phosphorylation of VE-cad.
authors: Department of Internal Medicine, Division of Cardiology, University of Texas Medical School at Houston, Houston, Texas 77030, USA. Mehran.Haidari@uth.tmc.edu
authors: Mehran
authors: M
authors: Haidari
authors: Wei
authors: W
authors: Zhang
authors: Amy
authors: A
authors: Caivano
authors: Zhenping
authors: Z
authors: Chen
authors: Leila
authors: L
authors: Ganjehei
authors: Ahmadreza
authors: A
authors: Mortazavi
authors: Christopher
authors: C
authors: Stroud
authors: Darren G
authors: DG
authors: Woodside
authors: James T
authors: JT
authors: Willerson
authors: Richard A F
authors: RA
authors: Dixon
mesh_terms: D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D038982:Integrin alpha2beta1 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D038982:Integrin alpha2beta1; D018994:Myosin Light Chains; D015689:Oncogene Protein p21(ras); D000099152:Cadherin 5