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Published 23 December 2002. doi:10.1083/jcb.200207070
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© The Rockefeller University Press, 0021-9525/2002/12/1061 $5.00
The Journal of Cell Biology, Volume 159, Number 6, 1061-1070

Article

 Regulation of Rac1 activation by the low density lipoprotein receptor–related protein

Zhong Ma1, Keena S. Thomas1, Donna J. Webb3, Radim Moravec2, Ana Maria Salicioni1, Wendy M. Mars4 and Steven L. Gonias1,2

1 Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908
2 Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908
3 Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908
4 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261

Address correspondence to Steven L. Gonias, Dept. of Pathology, University of Virginia School of Medicine, Box 800214, Charlottesville, VA 22908. Tel.: (434) 924-9192. Fax: (434) 982-0283. E-mail: slg2t{at}virginia.edu

The low density lipoprotein receptor–related protein (LRP-1) binds and mediates the endocytosis of multiple ligands, transports the urokinase-type plasminogen activator receptor (uPAR) and other membrane proteins into endosomes, and binds intracellular adaptor proteins involved in cell signaling. In this paper, we show that in murine embryonic fibroblasts (MEFs) and L929 cells, LRP-1 functions as a major regulator of Rac1 activation, and that this activity depends on uPAR. LRP-1–deficient MEFs demonstrated increased Rac1 activation compared with LRP-1–expressing MEFs, and this property was reversed by expressing the VLDL receptor, a member of the same gene family as LRP-1, with overlapping ligand-binding specificity. Neutralizing the activity of LRP-1 with receptor-associated protein (RAP) increased Rac1 activation and cell migration in MEFs and L929 cells. The same parameters were unaffected by RAP in uPAR-/- MEFs, prepared from uPAR gene knockout embryos, and in uPAR-deficient LM-TK- cells. Untreated uPAR+/+ MEFs demonstrated substantially increased Rac1 activation compared with uPAR-/- MEFs. In addition to Rac1, LRP-1 suppressed activation of extracellular signal–regulated kinase (ERK) in MEFs; however, it was Rac1 (and not ERK) that was responsible for the effects of LRP-1 on MEF migration. Thus, LRP-1 regulates two signaling proteins in the same cell (Rac1 and ERK), both of which may impact on cell migration. In uPAR-negative cells, LRP-1 neutralization does not affect Rac1 activation, and other mechanisms by which LRP-1 may regulate cell migration are not unmasked.

Key Words: urokinase-type plasminogen activator; uPAR; extracellular signal–regulated kinase; cell migration; VLDL receptor


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