Go to  Advanced Search

Please note that cIRcle is currently being upgraded to DSpace v5.1. The upgrade means that the cIRcle service will *not* be accepting new submissions from 5:00 PM on September 1, 2015 until 5:00 PM on September 4, 2015. All cIRcle material will still be accessible during this period. Apologies for any inconvenience.

The roles of integrin-linked kinase at the centrosome and its regulation of microtubule dynamics

Show full item record

Files in this item

Files Size Format Description   View
ubc_2012_spring_lim_simin.pdf 3.180Mb Adobe Portable Document Format   View/Open
Title: The roles of integrin-linked kinase at the centrosome and its regulation of microtubule dynamics
Author: Lim, Simin
Degree Master of Science - MSc
Program Interdisciplinary Oncology
Copyright Date: 2012
Publicly Available in cIRcle 2012-03-16
Abstract: Integrin-linked kinase (ILK) is both a scaffolding protein and a serine/threonine kinase that localizes to the focal adhesions. It interacts with the cytoplasmic domain of the β1-integrin subunit and acts as a hub for the localization of several actin cytoskeletal and signaling proteins resulting in the transduction of signals from cell-matrix interactions and growth factors into the cell interior. These signaling cascades go on to regulate important cellular processes such as cell migration, survival and proliferation. ILK has a second cellular localization at the centrosomes, where it regulates mitotic spindle organization and the interaction between ch-TOG, TACC3 and Aurora A, which is important for their function in regulating microtubule dynamics and spindle organization. However, the specific role of ILK's kinase activity, separate from a possible scaffolding role, in spindle organization is unclear. For this study, I attempted to characterize the spindle defect caused by QLT-0267, a small molecule inhibitor that is highly selective for ILK kinase activity. Treatment of HeLa cells with 10 μM QLT-0267 is known to result in a disorganized mitotic spindle that appeared arrested in a prometaphase-like phenotype. Here, I show that QLT-0267 exposure resulted in an increase in tension across sister centromeres aligned between two poles, suggesting a possible effect on spindle microtubule dynamics. Treatment with QLT-0267 was also associated with slower microtubule regrowth after depolymerization and the presence of a more stable population of microtubules in the mitotic spindle as evidenced by higher levels of acetylated α-tubulin. To further assess the role of ILK in regulating microtubule dynamics, the parameters of microtubule dynamic instability were measured in both QLT-0267-treated HeLa cells and ILK overexpressing HeLa cells. QLT-0267 appeared to dampen microtubule dynamic instability, while ILK overexpression enhanced it. ILK overexpression was also associated with decreased sensitivity to paclitaxel, a chemotherapeutic agent that stabilizes microtubule dynamics. Taken together, the results suggest a role for ILK's kinase activity in regulating microtubule dynamics. Finally, this study reports a novel mechanism of action for the small molecule inhibitor QLT-0267, which dampens microtubule dynamics and should be taken into consideration when designing future uses for the compound.
URI: http://hdl.handle.net/2429/41516
Scholarly Level: Graduate

This item appears in the following Collection(s)

Show full item record

All items in cIRcle are protected by copyright, with all rights reserved.

UBC Library
1961 East Mall
Vancouver, B.C.
Canada V6T 1Z1
Tel: 604-822-6375
Fax: 604-822-3893