PLCgamma1 is essential for early events in integrin signalling required for cell motility.
Date
2005-06ICR Author
Author
Jones, NP
Peak, J
Brader, S
Eccles, SA
Katan, M
Type
Journal Article
Metadata
Show full item recordAbstract
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, PLCgamma1, 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 PLCgamma1 to early, integrin-regulated changes leading to cell motility. The key role of PLCgamma1 was supported by findings that specific depletion of PLCgamma1 by small interfering (si)RNA, or by pharmacological inhibition, or the absence of this isoform in PLCgamma1(-/-) cells resulted in the failure to form cell protrusions and undergo cell spreading and elongation in response to integrin engagement. This integrin-PLCgamma1 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 PLCgamma1 activity, beta1 integrin and Src kinase are demonstrated to be essential for phosphorylation of PLCgamma1, 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 beta1 integrin or Src. Our findings establish PLCgamma1 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 PLCgamma1 in cell motility, functioning as a mediator of both growth factor and integrin-initiated signals.
Collections
Subject
Basement Membrane
Tumor Cells, Cultured
Extracellular Matrix
Fibroblasts
Endothelial Cells
Animals
Humans
Mice
Inositol 1,4,5-Trisphosphate
src-Family Kinases
Muscle Proteins
Integrins
RNA, Small Interfering
Signal Transduction
Cell Movement
Cell Shape
Calcium Signaling
Enzyme Activation
Phosphorylation
Time Factors
Phospholipase C gamma
Type C Phospholipases
Research team
Tumour Biology & Metastasis
Language
eng
License start date
2005-06
Citation
Journal of cell science, 2005, 118 (Pt 12), pp. 2695 - 2706