Molecular Biology of the Cell Call for Nominations: MBC Editor-in-Chief

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

MBC in Press, published online ahead of print November 17, 2004
Mol. Biol. Cell 10.1091/mbc.E04-06-0479

A more recent version of this article appeared on February 1, 2005
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
E04-06-0479v1
16/2/609    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Albig, A. R.
Right arrow Articles by Schiemann, W. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Albig, A. R.
Right arrow Articles by Schiemann, W. P.

Submitted on June 11, 2004
Revised on October 4, 2004
Accepted on November 4, 2004

Identification and Characterization of Regulator of G-Protein Signaling 4 (RGS4) as a Novel Inhibitor of Tubulogenesis: RGS4 Inhibits MAP Kinases and VEGF Signaling

Allan R. Albig and William P. Schiemann*

Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206

Monitoring Editor: Carl-Henrik Heldin

Tubulogenesis by epithelial cells regulates kidney, lung, and mammary development, while that by endothelial cells regulates vascular development. Although functionally dissimilar, the processes necessary for tubulation by epithelial and endothelial cells are quite similar. We performed microarray analysis to further our understanding of tubulogenesis and observed a robust induction of regulator of G-protein signaling 4 (RGS4) mRNA expression solely in tubulating cells, thereby implicating RGS4 as a potential regulator of tubulogenesis. Accordingly, RGS4 overexpression delayed and altered lung epithelial cell tubulation by selectively inhibiting G-protein-mediated p38 MAPK activation and, consequently, by reducing epithelial cell proliferation, migration, and expression of vascular endothelial growth factor (VEGF). The tubulogenic defects imparted by RGS4 in epithelial cells, including its reduction in VEGF expression, were rescued by overexpression of constitutively-active MKK6, an activator of p38 MAPK. Similarly, RGS4 overexpression abrogated endothelial cell angiogenic sprouting by inhibiting their synthesis of DNA and invasion through synthetic basement membranes. We further show that RGS4 expression antagonized VEGF stimulation of DNA synthesis and ERK1/ERK2 and p38 MAPK activation, as well as ERK1/ERK2 activation stimulated by endothelin-1 and angiotensin II. RGS4 had no effect on the phosphorylation of Smad1 and Smad2 by bone morphogenic protein-7 and transforming growth factor-{beta}, respectively, indicating that RGS4 selectively inhibits G-protein and VEGF signaling in endothelial cells. Finally, we found that RGS4 reduced endothelial cell response to VEGF by decreasing VEGF receptor-2 (KDR) expression. We therefore propose RGS4 as a novel antagonist of epithelial and endothelial cell tubulogenesis that selectively antagonizes intracellular signaling by G-proteins and VEGF, thereby inhibiting cell proliferation, migration, and invasion, and VEGF and KDR expression.

*Corresponding author. E-mail: schiemannwp{at}njc.org






Home Help [Feedback] [For Subscribers] [Archive] [Search] --
Copyright © 2004 by The American Society for Cell Biology. Terms of copyright protection, warranties, and disclaimers.