Abstract
The issue of how contractility and adhesion are related to cell shape and migration pattern remains largely unresolved. In this paper we report that Gleevec (Imatinib), an Abl family kinase inhibitor, produces a profound change in the shape and migration of rat bladder tumor cells (NBTII) plated on collagen-coated substrates. Cells treated with Gleevec adopt a highly spread D-shape and migrate more rapidly with greater persistence. Accompanying this more spread state is an increase in integrin-mediated adhesion coupled with increases in the size and number of discrete adhesions. In addition, both total internal reflection fluorescence microscopy (TIRFM) and interference reflection microscopy (IRM) revealed a band of small punctate adhesions with rapid turnover near the cell leading margin. These changes led to an increase in global cell-substrate adhesion strength, as assessed by laminar flow experiments. Gleevec-treated cells have greater RhoA activity which, via myosin activation, led to an increase in the magnitude of total traction force applied to the substrate. These chemical and physical alterations upon Gleevec treatment produce the dramatic change in morphology and migration that is observed.
Highlights
The study of cell migration is essential for understanding a variety of processes including wound repair, immune response and tissue homeostasis; importantly, aberrant cell migration can result in various pathologies [1,2,3]
We report that Gleevec, an Abl family kinase inhibitor that is used as a chemotherapeutic agent for leukemia, produces a profound change in the shape and migration of the rat Nara bladder tumor (NBT-II) cells plated on collagen-coated substrates
We observed that NBTII cells on collagen had medium-sized lamellae (Marked with ‘‘LM’’) and lamellipodia (Marked with ‘‘LP’’), some filopodia (Marked with ‘‘FP’’) dynamically formed at the leading edge of the cell, and multiple retraction fibers (Marked with ‘‘RF’’) formed at the trailing edge of the cell. (Figure 1A, Movie S1)
Summary
The study of cell migration is essential for understanding a variety of processes including wound repair, immune response and tissue homeostasis; importantly, aberrant cell migration can result in various pathologies [1,2,3]. Abl family tyrosine kinases are ubiquitous non-receptor tyrosine kinases (NRTKs) involved in signal transduction [4,5,6]. They can interact with other cellular components through multiple functional domains for filamentous and globular actin binding, as well as through binding phosphorylated tyrosines (SH2), polyproline rich regions (SH3), DNA (Abl), and microtubules (Abl Related Gene (Arg)) [7,8]. Abl family tyrosine kinases have been found to regulate cell migration [8,9]. A complete understanding of how Abl family kinases regulate cell migration is lacking [8,9]
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