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Vol. 18, Issue 4, 1220-1232, April 2007

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NHERF Links the N-Cadherin/Catenin Complex to the Platelet-derived Growth Factor Receptor to Modulate the Actin Cytoskeleton and Regulate Cell Motility

Department of Biochemistry and Molecular Biology, Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-7696

Submitted October 27, 2006; Revised December 26, 2006; Accepted January 5, 2007
Monitoring Editor: Martin A. Schwartz

Using phage display, we identified Na⁺/H⁺ exchanger regulatory factor (NHERF)-2 as a novel binding partner for the cadherin-associated protein, -catenin. We showed that the second of two PSD-95/Dlg/ZO-1 (PDZ) domains of NHERF interacts with a PDZ-binding motif at the very carboxy terminus of -catenin. N-cadherin expression has been shown to induce motility in a number of cell types. The first PDZ domain of NHERF is known to bind platelet-derived growth factor-receptor (PDGF-R), and the interaction of PDGF-R with NHERF leads to enhanced cell spreading and motility. Here we show that -catenin and N-cadherin are in a complex with NHERF and PDGF-R at membrane ruffles in the highly invasive fibrosarcoma cell line HT1080. Using a stable short hairpin RNA system, we showed that HT1080 cells knocked down for either N-cadherin or NHERF had impaired ability to migrate into the wounded area in a scratch assay, similar to cells treated with a PDGF-R kinase inhibitor. Cells expressing a mutant NHERF that is unable to associate with -catenin had increased stress fibers, reduced lamellipodia, and impaired cell migration. Using HeLa cells, which express little to no PDGF-R, we introduced PDGF-R and showed that it coimmunoprecipitates with N-cadherin and that PDGF-dependent cell migration was reduced in these cells when we knocked-down expression of N-cadherin or NHERF. These studies implicate N-cadherin and -catenin in cell migration via PDGF-R–mediated signaling through the scaffolding molecule NHERF.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Margaret J. Wheelock (mwheelock{at}unmc.edu)

Abbreviations used: NHERF, Na⁺/H⁺ exchanger regulatory factor; PDZ, PSD-95/Dlg/ZO-1; PDGF-R, platelet-derived growth factor receptor.