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Molecular and Cellular Biology, November 2009, p. 5963-5973, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.01268-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Modulation of Rho Guanine Exchange Factor Lfc Activity by Protein Kinase A-Mediated Phosphorylation{triangledown}

David Meiri,1,{dagger} Melissa A. Greeve,1,{dagger} Andrea Brunet,1 Dina Finan,1 Clark D. Wells,2 Jose LaRose,1 and Robert Rottapel1,2,3*

Ontario Cancer Institute, Toronto Medical Discovery Tower, 101 College St., Toronto, Ontario M5G 1L7, Canada,1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada,2 Departments of Medical Biophysics and Medicine and Immunology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada3

Received 10 August 2008/ Returned for modification 3 October 2008/ Accepted 23 July 2009

Lfc is a guanine nucleotide exchange factor (GEF) for Rho that demonstrates an unusual ability to associate with microtubules. While several phosphorylated residues have been detected in the Lfc polypeptide, the mechanism(s) by which phosphorylation regulates the exchange activity of Lfc remains unclear. We confirm that Lfc is a phosphorylated protein and demonstrate that 14-3-3 interacts directly and in a phosphorylation-dependent manner with Lfc. We identify AKAP121 as an Lfc-binding protein and show that Lfc is phosphorylated in an AKAP-dependent manner by protein kinase A (PKA). Forskolin treatment induced 14-3-3 binding to Lfc and suppressed the exchange activity of wild-type Lfc on RhoA. Importantly, a mutant of Lfc that is unable to associate with 14-3-3 proteins was resistant to inhibition by forskolin. Tctex-1, a dynein motor light chain, binds to Lfc in a competitive manner with 14-3-3.

* Corresponding author. Mailing address: Ontario Cancer Institute, Toronto Medical Discovery Tower, MaRS East Tower, 101 College St., Toronto, Ontario M5G 1L7, Canada. Phone: (416) 581-7852. Fax: (416) 599-5719. E-mail: rottapel{at}uhnresearch.ca

{triangledown} Published ahead of print on 10 August 2009.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, November 2009, p. 5963-5973, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.01268-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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