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J. Biol. Chem., Vol. 282, Issue 10, 7232-7241, March 9, 2007

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Identification of a Novel Domain at the N Terminus of Caveolin-1 That Controls Rear Polarization of the Protein and Caveolae Formation^*

Xing-Hui Sun, Daniel C. Flynn^¶, Vincent Castranova^||, Lyndell L. Millecchia^||, Andrew R. Beardsley, and Jun Liu^¶1

From the Departments of Physiology and Pharmacology and Microbiology, Immunology, and Cell Biology and the ^¶Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506 and the ^||Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505

When cells are migrating, caveolin-1, the principal protein component of caveolae, is excluded from the leading edge and polarized at the cell rear. The dynamic feature depends on a specific sequence motif that directs intracellular trafficking of the protein. Deletion mutation analysis revealed a putative polarization domain at the N terminus of caveolin-1, between amino acids 32–60. Alanine substitution identified a minimal sequence of 10 residues (⁴⁶TKEIDLVNRD⁵⁵) necessary for caveolin-1 rear polarization. Interestingly, deletion of amino acids 1–60 did not prevent the polarization of caveolin-1 in human umbilical vein endothelial cells or wild-type mouse embryonic fibroblasts because of an interaction of Cav_61–178 mutant with endogenous caveolin-1. Surprisingly, expression of the depolarization mutant in caveolin-1 null cells dramatically impeded caveolae formation. Furthermore, knockdown of caveolae formation by methyl--cyclodextrin failed to prevent wild-type caveolin-1 rear polarization. Importantly, genetic depletion of caveolin-1 led to disoriented migration, which can be rescued by full-length caveolin-1 but not the depolarization mutant, indicating a role of caveolin-1 polarity in chemotaxis. Thus, we have identified a sequence motif that is essential for caveolin-1 rear polarization and caveolae formation.

Received for publication, August 3, 2006 , and in revised form, December 18, 2006.

^* This work was supported by Grant RR016440 from the National Institutes of Health (to J. L. and D. C. F.) and the Sara and James Allen Lung Cancer Funds (to J. L.). 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.

¹ To whom correspondence should be addressed: West Virginia University Health Science Center, Dept. of Physiology and Pharmacology, P. O. Box 9229, Morgantown, WV 26506-9229. Tel.: 304-293-1503; Fax: 304-293-3850; E-mail: junliu{at}hsc.wvu.edu.

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