Published online before print May 4, 2006, doi: 10.1161/01.RES.0000225283.71490.5a
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on November 5, 2005
Revised on March 15, 2006
Accepted on April 20, 2006
Syndecan-4 Clustering Induces Cell Migration in a PDZ-Dependent Manner
Eugene Tkachenko ;
From the Angiogenesis Research Center, Section of Cardiology, Departments of Medicine and Pharmacology and Toxicology, Dartmouth Medical School, Lebanon, NH.
* To whom correspondence should be addressed. E-mail: Michael.Simons{at}Dartmouth.edu.
Cell migration is a dynamic process involving formation of a leading edge in the direction of migration and adhesion points from which tension is generated to move the cell body forward. At the same time, disassembly of adhesion points occurs at the back of the cell, a region known as the trailing edge. Syndecan-4 (S4) is a transmembrane proteoglycan thought to be involved in the formation of focal adhesions. Recent studies have shown that its cytoplasmic domain can engage in signal transduction, making S4 a bona fide receptor. Here, we show that ligand clustering of cell surface S4 on endothelial cells initiates a signaling cascade that results in activation of Rac1, induction of cell polarization, and stimulation of cell migration that depends on S4 interaction with its PDZ-binding partner. Expression of an S4 mutant lacking its PDZ-binding region (S4-PDZ-) leads to decreased cell motility and a failure to form a trailing edge. On clustering S4, but not S4-PDZ-, targets activated Rac1 to the leading edge of live cells. Cells lacking synectin, a PDZ domain containing protein that interacts with S4, fail to migrate in response to S4 clustering. Both S4-PDZ--expressing and synectin-/- endothelial cells exhibit elevated basal levels of Rac1. Thus, our data suggest that S4 promotes endothelial cell migration in response to ligand binding by activating Rac1 and localizing it to the leading edge, and that these processes are dependent on its PDZ-binding domain interaction with synectin.
Key words: syndecan • synectin • migration • endothelial cells • Rac1 • PDZ
This article has been cited by other articles:
 |
|
 |
|
  E. Baljinnyam, K. Iwatsubo, R. Kurotani, X. Wang, C. Ulucan, M. Iwatsubo, D. Lagunoff, and Y. Ishikawa Epac increases melanoma cell migration by a heparan sulfate-related mechanism Am J Physiol Cell Physiol, October 1, 2009; 297(4): C802 - C813. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Elfenbein, J. M. Rhodes, J. Meller, M. A. Schwartz, M. Matsuda, and M. Simons Suppression of RhoG activity is mediated by a syndecan 4-synectin-RhoGDI1 complex and is reversed by PKC{alpha} in a Rac1 activation pathway J. Cell Biol., July 13, 2009; 186(1): 75 - 83. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Bass, M. R. Morgan, K. A. Roach, J. Settleman, A. B. Goryachev, and M. J. Humphries p190RhoGAP is the convergence point of adhesion signals from {alpha}5{beta}1 integrin and syndecan-4 J. Cell Biol., October 21, 2008; 181(6): 1013 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Murakami, A. Elfenbein, and M. Simons Non-canonical fibroblast growth factor signalling in angiogenesis Cardiovasc Res, May 1, 2008; 78(2): 223 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Bass, K. A. Roach, M. R. Morgan, Z. Mostafavi-Pour, T. Schoen, T. Muramatsu, U. Mayer, C. Ballestrem, J. P. Spatz, and M. J. Humphries Syndecan-4-dependent Rac1 regulation determines directional migration in response to the extracellular matrix J. Cell Biol., May 7, 2007; 177(3): 527 - 538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Lanahan, T. W. Chittenden, E. Mulvihill, K. Smith, S. Schwartz, and M. Simons Synectin-dependent gene expression in endothelial cells Physiol Genomics, November 21, 2006; 27(3): 380 - 390. [Abstract] [Full Text] [PDF]
|
|