Requirement of alpha and beta subunit transmembrane helix separation for integrin outside-in signaling. Blood 2007 Oct 01;110(7):2475-83
Date
07/07/2007Pubmed ID
17615290Pubmed Central ID
PMC1988953DOI
10.1182/blood-2007-03-080077Scopus ID
2-s2.0-34948882323 (requires institutional sign-in at Scopus site) 103 CitationsAbstract
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 beta 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 alphaIIbbeta3 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.
Author List
Zhu J, Carman CV, Kim M, Shimaoka M, Springer TA, Luo BHAuthor
Jieqing Zhu PhD Assistant Professor, Associate Investigator in the Biochemistry department at BloodCenter of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Adhesion
Cell Line
Cell Membrane
Cricetinae
Disulfides
Enzyme Activation
Focal Adhesion Protein-Tyrosine Kinases
Humans
Ligands
Mutation
Phosphotyrosine
Platelet Glycoprotein GPIIb-IIIa Complex
Protein Subunits
Signal Transduction
Solubility
