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First published online June 8, 2005
doi: 10.1242/10.1242/jcs.02374
Research Article |
1 is essential for early events in integrin signalling required for cell motility
1 Cancer Research UK Centre for Cell and Molecular Biology, Chester Beatty Laboratories, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK
2 Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK
* Author for correspondence (e-mail: matilda{at}icr.ac.uk)
Accepted 10 March 2005
Cell motility is a critical event in many processes and is underlined by complex signalling interactions. Although many components have been implicated in different forms of cell migration, identification of early key mediators of these events has proved difficult. One potential signalling intermediate, PLC
1, has previously been implicated in growth-factor-mediated chemotaxis but its position and roles in more-complex motility events remain poorly understood. This study links PLC1 to early, integrin-regulated changes leading to cell motility. The key role of PLC1 was supported by findings that specific depletion of PLC1 by small interfering (si)RNA, or by pharmacological inhibition, or the absence of this isoform in PLC1–/– cells resulted in the failure to form cell protrusions and undergo cell spreading and elongation in response to integrin engagement. This integrin-PLC1 pathway was shown to underlie motility processes involved in morphogenesis of endothelial cells on basement membranes and invasion of cancer cells into such three-dimensional matrices. By combining cellular and biochemical approaches, we have further characterized this signalling pathway. Upstream of PLC1 activity, ß1 integrin and Src kinase are demonstrated to be essential for phosphorylation of PLC1, formation of protein complexes and accumulation of intracellular calcium. Cancer cell invasion and the early morphological changes associated with cell motility were abolished by inhibition of ß1 integrin or Src. Our findings establish PLC1 as a key player in integrin-mediated cell motility processes and identify other critical components of the signalling pathway involved in establishing a motile phenotype. This suggests a more general role for PLC1 in cell motility, functioning as a mediator of both growth factor and integrin-initiated signals.
Key words: PLC1, Signalling, Motility, Extracellular matrix
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