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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.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Requirement of {alpha} and ß subunit transmembrane helix separation for integrin outside-in signaling

Jieqing Zhu1, Christopher V. Carman2, Minsoo Kim3, Motomu Shimaoka4, Timothy A. Springer1, and Bing-Hao Luo1

1 The CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, 2 Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA; 3 Division of Surgical Research, Rhode Island Hospital, Brown University School of Medicine, Providence; 4 The CBR Institute for Biomedical Research and Department of Anesthesia, Harvard Medical School, Boston, MA

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 {alpha} and ß 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 intersubunit disulfide bond, we generated mutant integrin {alpha}IIbß3 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.


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 J. Biol. Chem.Home page
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.
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