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The very low density lipoprotein receptor regulates urokinase receptor catabolism and breast cancer cell motility in vitro.

Abstract
The very low density lipoprotein receptor (VLDLr) binds diverse ligands, including urokinase-type plasminogen activator (uPA) and uPA-plasminogen activator inhibitor-1 (PAI-1) complex. In this study, we characterized the effects of the VLDLr on the internalization, catabolism, and function of the uPA receptor (uPAR) in MCF-7 and MDA-MB-435 breast cancer cells. When challenged with uPA.PAI-1 complex, MDA-MB-435 cells internalized uPAR; this process was inhibited by 80% when the activity of the VLDLr was neutralized with receptor-associated protein (RAP). To determine whether internalized uPAR is degraded, we studied the catabolism of [35S]methionine-labeled uPAR. In the absence of exogenous agents, the uPAR catabolism t(1)/(2) was 8.2 h. uPA.PAI-1 complex accelerated uPAR catabolism (t(1)/(2) to 1.8 h), while RAP inhibited uPAR catabolism in the presence (t(1)/(2) of 7.8 h) and absence (t(1)/(2) of 16.9 h) of uPA.PAI-1 complex, demonstrating a critical role for the VLDLr. When MCF-7 cells were cultured in RAP, cell surface uPAR levels increased gradually, reaching a new steady-state in 3 days. The amount of uPA which accumulated in the medium also increased. Culturing in RAP for 3 days increased MCF-7 cell motility by 2.2 +/- 0.1-fold and by 4.4 +/- 0.3-fold when 1.0 nM uPA was added. The effects of RAP on MCF-7 cell motility were entirely abrogated by an antibody which binds uPA and prevents uPA binding to uPAR. MCF-7 cells that were cultured in RAP demonstrated increased levels of activated mitogen-activated protein kinases. Furthermore, the MEK inhibitor, PD098059, decreased the motility of RAP-treated cells without affecting control cultures. These studies suggest a model in which the VLDLr regulates autocrine uPAR-initiated signaling and thereby regulates cellular motility.
AuthorsD J Webb, D H Nguyen, M Sankovic, S L Gonias
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 274 Issue 11 Pg. 7412-20 (Mar 12 1999) ISSN: 0021-9258 [Print] United States
PMID10066806 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Carrier Proteins
  • Lipoproteins, VLDL
  • PLAUR protein, human
  • Receptors, Cell Surface
  • Receptors, LDL
  • Receptors, Urokinase Plasminogen Activator
  • Recombinant Fusion Proteins
  • VLDL receptor
  • GST-RAP protein, recombinant
  • Glutathione Transferase
  • Calcium-Calmodulin-Dependent Protein Kinases
Topics
  • Breast Neoplasms (enzymology, metabolism, pathology)
  • Calcium-Calmodulin-Dependent Protein Kinases (metabolism)
  • Carrier Proteins (metabolism)
  • Cell Movement (physiology)
  • Endocytosis
  • Enzyme Activation
  • Glutathione Transferase (metabolism)
  • Humans
  • Hydrolysis
  • Lipoproteins, VLDL (metabolism)
  • Receptors, Cell Surface (metabolism)
  • Receptors, LDL (metabolism, physiology)
  • Receptors, Urokinase Plasminogen Activator
  • Recombinant Fusion Proteins (metabolism)
  • Tumor Cells, Cultured

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