Requirement of alpha and beta subunit transmembrane helix separation for integrin outside-in signaling.

Abstract:

: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.

journal_name

Blood

journal_title

Blood

authors

Zhu J,Carman CV,Kim M,Shimaoka M,Springer TA,Luo BH

doi

10.1182/blood-2007-03-080077

subject

Has Abstract

pub_date

2007-10-01 00:00:00

pages

2475-83

issue

7

eissn

0006-4971

issn

1528-0020

pii

blood-2007-03-080077

journal_volume

110

pub_type

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