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Threonine 788 in integrin subunit β1 regulates integrin activation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2006 (English)In: Exp Cell Res., Vol. 312, no 6, 844-853 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 312, no 6, 844-853 p.
URN: urn:nbn:se:uu:diva-94274OAI: oai:DiVA.org:uu-94274DiVA: diva2:168066
Available from: 2006-04-12 Created: 2006-04-12 Last updated: 2011-06-28Bibliographically approved
In thesis
1. Structural and Functional Aspects of β1 Integrin Signalling
Open this publication in new window or tab >>Structural and Functional Aspects of β1 Integrin Signalling
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Integrins are transmembrane glycoproteins primarily mediating interactions of cells with the extracellular matrix. Each receptor is a complex of one α- and one β-subunit with affinity for a diverse set of ligands. A prerequisite for ligand binding, and subsequent events, is the activation of integrins by cytoplasmic signals that confer a large conformational change to the extracellular domain.

In this thesis, the role of a cytoplasmic threonine-cluster, conserved in several β subunits, in β1-integrin activation was investigated. Phosphorylation of these residues is postulated to regulate β2 and β3 integrin affinity for ligands, but it has not been shown so far to occur for β1. Residue T788, but not T789, was established as a site of critical importance for inside-out activation of β1 integrins by mutagenesis to alanine. In contrast to β1-T788A, a phospho-mimicking mutation, β1-T788D, expressed the conformation sensitive 9EG7-epitope and mediated normal cell adhesion. In addition, the T788D mutation did not interfere with binding of the talin head domain, an interaction important for integrin activation. Thus, phosphorylation of T788 in integrin β1 was concluded to be compatible with inside-out receptor activation, in line with β2 and β3 integrin regulation.

Focal adhesion kinase (FAK) is activated after integrin ligation and is, together with Src, one of the central players in integrin-mediated events. Phosphatidylinositol 3-kinase (PI3K) is thought to be activated by binding to FAK. However, a novel, major β1-integrin signalling pathway to activate PI3K was identified, which is FAK- and Src-independent.

Growth factor induced stimulation of extracellular signal-regulated kinase (Erk) is largely dependent on signals from integrin mediated adhesion to pass checkpoints downstream of Ras. The mechanisms by which β1-integrins mediate Erk-activation were characterized by pin-pointing what phosphorylation sites on the mitogen-activated protein (MAP) kinases and their effector proteins were FAK-dependent. The results indicated that β1 integrins can promote Erk activation by FAK-dependent mechanisms at the levels of both cRaf and Mek, and in addition, a FAK-independent checkpoint at the level of Mek activation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 69 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 136
Cell and molecular biology, Integrin, Integrin subunit β1, Integrin activation, Threonine, Phosphorylation, Integrin signalling, FAK, PI3K, MAPK, Cell- och molekylärbiologi
urn:nbn:se:uu:diva-6747 (URN)91-554-6529-3 (ISBN)
Public defence
2006-05-05, B42, Biomedicinskt centrum, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2006-04-12 Created: 2006-04-12Bibliographically approved

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Johansson, Staffan
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