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Molecular and Cellular Biology, December 2007, p. 8683-8697, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.00157-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Nuclear RhoA Exchange Factor Net1 Interacts with Proteins of the Dlg Family, Affects Their Localization, and Influences Their Tumor Suppressor Activity{triangledown} ,{dagger}

Rafael García-Mata,1* Adi D. Dubash,1 Lisa Sharek,1 Heather S. Carr,2 Jeffrey A. Frost,2 and Keith Burridge1

Department of Cell and Developmental Biology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,1 Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, Texas2

Received 26 January 2007/ Returned for modification 5 March 2007/ Accepted 1 October 2007

Net1 is a RhoA-specific guanine nucleotide exchange factor which localizes to the nucleus at steady state. A deletion in its N terminus redistributes the protein to the cytosol, where it activates RhoA and can promote transformation. Net1 contains a PDZ-binding motif at the C terminus which is essential for its transformation properties. Here, we found that Net1 interacts through its PDZ-binding motif with tumor suppressor proteins of the Dlg family, including Dlg1/SAP97, SAP102, and PSD95. The interaction between Net1 and its PDZ partners promotes the translocation of the PDZ proteins to nuclear subdomains associated with PML bodies. Interestingly, the oncogenic mutant of Net1 is unable to shuttle the PDZ proteins to the nucleus, although these proteins still associate as clusters in the cytosol. Our results suggest that the ability of oncogenic Net1 to transform cells may be in part related to its ability to sequester tumor suppressor proteins like Dlg1 in the cytosol, thereby interfering with their normal cellular function. In agreement with this, the transformation potential of oncogenic Net1 is reduced when it is coexpressed with Dlg1 or SAP102. Together, our results suggest that the interaction between Net1 and Dlg1 may contribute to the mechanism of Net1-mediated transformation.

* Corresponding author. Mailing address: Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, 12-026 Lineberger, CB#7295, Chapel Hill, NC 27599. Phone: (919) 966-5783. Fax: (919) 966-3015. E-mail: rafaelgm{at}med.unc.edu

{triangledown} Published ahead of print on 15 October 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2007, p. 8683-8697, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.00157-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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