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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2475-2483. Prepublished online as a Blood First Edition Paper on July 5, 2007; DOI 10.1182/blood-2007-03-080077. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-03-080077v1 110/7/2475    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhu, J. Articles by Luo, B.-H. Search for Related Content PubMed PubMed Citation Articles by Zhu, J. Articles by Luo, B.-H. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 15, 2007 Accepted June 19, 2007 Requirement of and subunit transmembrane helix separation for integrin outside-in signaling Jieqing Zhu, Christopher V Carman, Minsoo Kim, Motomu Shimaoka, Timothy A Springer, and Bing-Hao Luo* The CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA Beth Israel Deaconess Medical Center, Dept of Medicine, Harvard Medical School, Boston, MA Division of surgical Research, Rhode Island Hospital, Brown University School of Medicine, Providence, RI Dept of Anesthesia, Harvard Medical School, Boston, MA Dept of Pathology, Harvard Medical School, Boston, MA * Corresponding author; email: luo{at}lsu.edu. Adhesion to extracellular ligands through integrins regulates cell shape, migration, growth and survival. How integrins transmit signals in the outside-to-in direction remains unknown. Whereas in resting integrins the and subunit transmembrane domains are associated, ligand binding promotes dissociation and separation of these domains. Here we address whether such separation is required for outside-in signaling. By introduction of an inter-subunit disulfide bond, we generated mutant integrin IIb3 with blocked transmembrane separation that binds ligand, mediates adhesion, adopts an extended conformation after ligand binding, and forms antibody-induced macroclusters on the cell surface similarly to wild-type. However, the mutant integrin exhibits a profound defect in adhesion-induced outside-in signaling as measured by cell spreading, actin stress fiber and focal adhesion formation and focal adhesion kinase activation. This defect was rescued by reduction of the disulfide bond. Our results demonstrate that the separation of transmembrane domains is required for integrin outside-in signal transduction. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Lindert, M. Silvestry, T.-M. Mullen, G. R. Nemerow, and P. L. Stewart Cryo-Electron Microscopy Structure of an Adenovirus-Integrin Complex Indicates Conformational Changes in both Penton Base and Integrin J. Virol., November 15, 2009; 83(22): 11491 - 11501. [Abstract] [Full Text] [PDF] C. T. Lefort, Y.-M. Hyun, J. B. Schultz, F.-Y. Law, R. E. Waugh, P. A. Knauf, and M. Kim Outside-In Signal Transmission by Conformational Changes in Integrin Mac-1 J. Immunol., November 15, 2009; 183(10): 6460 - 6468. [Abstract] [Full Text] [PDF] C. Kim, T.-L. Lau, T. S. Ulmer, and M. H. Ginsberg Interactions of platelet integrin {alpha}IIb and {beta}3 transmembrane domains in mammalian cell membranes and their role in integrin activation Blood, May 7, 2009; 113(19): 4747 - 4753. [Abstract] [Full Text] [PDF] B.-H. Luo, J. Karanicolas, L. D. Harmacek, D. Baker, and T. A. Springer Rationally Designed Integrin {beta}3 Mutants Stabilized in the High Affinity Conformation J. Biol. Chem., February 6, 2009; 284(6): 3917 - 3924. [Abstract] [Full Text] [PDF] A. Vararattanavech, X. Lin, J. Torres, and S.-M. Tan Disruption of the Integrin {alpha}L{beta}2 Transmembrane Domain Interface by {beta}2 Thr-686 Mutation Activates {alpha}L{beta}2 and Promotes Micro-clustering of the {alpha}L Subunits J. Biol. Chem., January 30, 2009; 284(5): 3239 - 3249. [Abstract] [Full Text] [PDF] M.-L. Tang, A. Vararattanavech, and S.-M. Tan Urokinase-type Plasminogen Activator Receptor Induces Conformational Changes in the Integrin {alpha}M{beta}2 Headpiece and Reorientation of Its Transmembrane Domains J. Biol. Chem., September 12, 2008; 283(37): 25392 - 25403. [Abstract] [Full Text] [PDF] T.-L. Lau, V. Dua, and T. S. Ulmer Structure of the Integrin {alpha}IIb Transmembrane Segment J. Biol. Chem., June 6, 2008; 283(23): 16162 - 16168. [Abstract] [Full Text] [PDF] J. G. Goetz, B. Joshi, P. Lajoie, S. S. Strugnell, T. Scudamore, L. D. Kojic, and I. R. Nabi Concerted regulation of focal adhesion dynamics by galectin-3 and tyrosine-phosphorylated caveolin-1 J. Cell Biol., March 24, 2008; 180(6): 1261 - 1275. [Abstract] [Full Text] [PDF]

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