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Published online August 18, 2008
doi:10.1083/jcb.200801133
The Journal of Cell Biology, Vol. 182, No. 4, 727-739
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Valiyaveettil et al.
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Article

Novel role of the muskelin–RanBP9 complex as a nucleocytoplasmic mediator of cell morphology regulation



Manojkumar Valiyaveettil1, Amber A. Bentley1, Priya Gursahaney1, Rajaa Hussien1, Ritu Chakravarti1, Nina Kureishy2, Soren Prag1,2, and Josephine C. Adams1,2,3

1 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
2 Medical Research Council Laboratory for Molecular Cell Biology and Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, England, UK
3 Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH 44195

Correspondence to Josephine C. Adams: adamsj{at}ccf.org

The evolutionarily conserved kelch-repeat protein muskelin was identified as an intracellular mediator of cell spreading. We discovered that its morphological activity is controlled by association with RanBP9/RanBPM, a protein involved in transmembrane signaling and a conserved intracellular protein complex. By subcellular fractionation, endogenous muskelin is present in both the nucleus and the cytosol. Muskelin subcellular localization is coregulated by its C terminus, which provides a cytoplasmic restraint and also controls the interaction of muskelin with RanBP9, and its atypical lissencephaly-1 homology motif, which has a nuclear localization activity which is regulated by the status of the C terminus. Transient or stable short interfering RNA–based knockdown of muskelin resulted in protrusive cell morphologies with enlarged cell perimeters. Morphology was specifically restored by complementary DNAs encoding forms of muskelin with full activity of the C terminus for cytoplasmic localization and RanBP9 binding. Knockdown of RanBP9 resulted in equivalent morphological alterations. These novel findings identify a role for muskelin–RanBP9 complex in pathways that integrate cell morphology regulation and nucleocytoplasmic communication.

M. Valiyaveettil, A.A. Bentley, and P. Gursahaney contributed equally to this paper.

M. Valiyaveettil's present address is Novo Nordisk Research United States, North Brunswick, NJ 08902.

S. Prag's present address is Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.

Abbreviations used in this paper: crm1, chromosome maintenance region 1; CTLH, C-terminal to LisH; DD, discoidin-like domain; FN, fibronectin; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; LIS1, lissencephaly-1; LisH, LIS1 homology; NES, nuclear export sequence; shRNA, short hairpin RNA; SMART, simple modular architecture research tool; TSP-1, thrombospondin-1.

© 2008 Valiyaveettil et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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