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Molecular and Cellular Biology, July 2002, p. 4690-4701, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4690-4701.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Targeting Protein Phosphatase 1 (PP1) to the Actin Cytoskeleton: the Neurabin I/PP1 Complex Regulates Cell Morphology

Carey J. Oliver,1 Ryan T. Terry-Lorenzo,1 Elizabeth Elliott,2 Wendy A. Christensen Bloomer,1 Shi Li,1 David L. Brautigan,2 Roger J. Colbran,3 and Shirish Shenolikar1*

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710,1 Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908,2 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 372323

Received 23 January 2002/ Returned for modification 6 March 2002/ Accepted 25 March 2002

Neurabin I, a neuronal actin-binding protein, binds protein phosphatase 1 (PP1) and p70 ribosomal S6 protein kinase (p70S6K), both proteins implicated in cytoskeletal dynamics. We expressed wild-type and mutant neurabins fused to green fluorescent protein in Cos7, HEK293, and hippocampal neurons. Biochemical and cellular studies showed that an N-terminal F-actin-binding domain dictated neurabin I localization at actin cytoskeleton and promoted disassembly of stress fibers. Deletion of the C-terminal coiled-coil and sterile alpha motif domains abolished neurabin I dimerization and induced filopodium extension. Immune complex assays showed that neurabin I recruited an active PP1 via a PP1-docking sequence,457KIKF460. Mutation of the PP1-binding motif or PP1 inhibition by okadaic acid and calyculin A abolished filopodia and restored stress fibers in cells expressing neurabin I. In vitro and in vivo studies suggested that the actin-binding domain attenuated protein kinase A (PKA) phosphorylation of neurabin I. Modification of a major PKA site, serine-461, impaired PP1 binding. Finally, p70S6K was excluded from neurabin I/PP1 complexes and required the displacement of PP1 for recruitment to neurabin I. These studies provided new insights into the assembly and regulation of a neurabin I/PP1 complex that controls actin rearrangement to promote spine development in mammalian neurons.

* Corresponding author. Mailing address: Department of Pharmacology and Cancer Biology, Duke University Medical Center, LSRC C315, Research Drive, Durham, NC 27710. Phone: (919) 681-6178. Fax: (919) 681-9567. E-mail: sheno001{at}mc.duke.edu.

Molecular and Cellular Biology, July 2002, p. 4690-4701, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4690-4701.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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