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J. Biol. Chem., Vol. 279, Issue 23, 24420-24426, June 4, 2004

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Formin Homology Domain Protein (FHOD1) Is a Cyclic GMP-dependent Protein Kinase I-binding Protein and Substrate in Vascular Smooth Muscle Cells^*

Yuepeng Wang, Mohamad R. El-Zaru, Howard K. Surks, and Michael E. Mendelsohn

From the Molecular Cardiology Research Institute, Department of Medicine and Division of Cardiology, New England Medical Center Hospitals and Tufts University School of Medicine, Boston, Massachusetts 02111

Cyclic GMP-dependent protein kinase I (PKGI) mediates vascular relaxation by nitric oxide and related nitrovasodilators and inhibits vascular smooth muscle cell (VSMC) migration. To identify VSMC proteins that interact with PKGI, the N-terminal protein interaction domain of PKGI was used to screen a yeast two-hybrid human aortic cDNA library. The formin homology (FH) domain-containing protein, FHOD1, was found to interact with PKGI in this screen. FH domain-containing proteins bind Rho-family GTPases and regulate actin cytoskeletal dynamics, cell migration, and gene expression. Antisera to FHOD1 were raised and used to characterize FHOD1 expression and distribution in vascular cells. FHOD1 is highly expressed in human coronary artery, aortic smooth muscle cells, and in human arterial and venous endothelial cells. In glutathione S-transferase pull-down experiments, the FHOD1 C terminus (amino acids 964–1165) binds full-length PKGI. Both in vitro and intact cell studies demonstrate that the interaction between FHOD1 and PKGI is decreased 3- to 5-fold in the presence of the PKG activator, 8Br-cGMP. Immunofluorescence studies of human VSMC show that FHOD1 is cytoplasmic and is concentrated in the perinuclear region. PKGI also directly phosphorylates FHOD1, and studies with wild-type and mutant FHOD1-derived peptides identify Ser-1131 in the FHOD1 C terminus as the unique PKGI phosphorylation site in FHOD1. These studies demonstrate that FHOD1 is a PKGI-interacting protein and substrate in VSMCs and show that cyclic GMP negatively regulates the FHOD1-PKGI interaction. Based on the known functions of FHOD1, the data are consistent with a role for FHOD1 in cyclic GMP-dependent inhibition of VSMC stress fiber formation and/or migration.

Received for publication, December 17, 2003 , and in revised form, March 10, 2004.

^* This work was supported in part by National Institutes of Health Grant R01 HL55309 (to M. E. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Tufts University School of Medicine, New England Medical Center, Molecular Cardiology Research Institute, 750 Washington St., Box 80, Boston, MA 02111. Tel.: 617-636-9370; Fax: 617-636-1444; E-mail: mmendelsohn{at}tuftsnemc.org.

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