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Title: Regulation of integrin activation and migration in fibroblasts
Author: Kemp-O'Brien, Karl William
ISNI:       0000 0004 5368 1604
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2014
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Cell adhesion and migration is essential for normal tissue organisation and function and dysregulation of these processes is involved in a number of different diseases. Focal adhesions are the major sites of adhesion to the extracellular matrix in migrating cells and integrins are a major component of these structures. Integrins are heterodimeric transmembrane receptors that undergo cycles of activation and inactivation at the plasma membrane to control assembly of focal adhesions. Integrins can be activated in two different ways; outside-in activation by binding to an extracellular ligand, or inside-out activation though the binding of cytoplasmic proteins to the integrin cytoplasmic tail. Talin and kindlin proteins are the two known families of activators of integrins, and act through binding to the cytoplasmic tail on the integrin beta subunit. Both kindlins and talin contain phospholipid-binding domains and have been shown biochemically to be able to bind to PIP2 or PIP3. The aim of this study is to characterize the recruitment of talin and kindlins to integrins and their individual roles in the sequence of receptor activation. The role of PIP2 and PIP3 in regulating the recruitment of integrin activators to adhesion sites and the role of each of these protein families in controlling integrin dynamics at focal adhesions was also addressed in fibroblast cells on both 2D and 3D matrices. Data demonstrates that kindlin2 plays the key role in fibroblast migration on 2D and 3D matrices and that this correlates with a reduction in active integrin levels. Moreover, live cell imaging revealed that kindlins appear at focal adhesions prior to talin suggesting a role for these proteins in ‘priming’ the receptor for activation by talin. Finally, these recruitment and adhesion maturation events all depend on the balance of PIP2 local to focal adhesions. These findings shed novel light on the mechanism of integrin activation in migrating cells.
Supervisor: Parsons, Madeline ; Ameer-Beg, Simon Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available