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Title: Activation of LFA-1 through mutations within the IDAS site of the I domain : their effects on ligand binding and the capacity of LFA-1 to signal to other integrins
Author: Sweeney, Bernadette Mary
ISNI:       0000 0001 3493 7107
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2004
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Evidence is now emerging which suggests that in addition to the ability of integrins to regulate cell adhesion through signalling events to other cell surface receptors they may also play a role in the regulation of other integrins expressed on the same cell surface. While the data on LFA-1 is limited, published reports suggest that this integrin when activated can both down- and up-regulate the binding of α4β1 and α5β1 to their respective ligands. Using a novel method we expressed a soluble form of LFA-1 which was subsequently used to identify a series of constitutively activated forms of LFA-1 generated through introduction of novel and published mutations into the I Domain IDAS. Having established their increased activity over wild type LFA-1, the mutant forms of LFA-1 were used to investigate the ability of full length LFA-1 to regulate the binding of α4β1 and α5β1 when expressed on the same cell surface. While mutations in the LFA-1 I domain currently known to promote ligand binding were not sufficient alone to promote integrin crosstalk in either the K562 or JB2.7 cell systems, in the presence of mAb KIM127, crosstalk between α5β1 and all forms of K562 surface expressed LFA-1 was effectively induced. However, the lack of crosstalk with the JB2.7 cell line, even in the presence of K1M127, suggests that this phenomenon may be further complicated by cell-line specific differences.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral