PLCγ1 is essential for early events in integrin signalling required for cell motility

被引:86
作者
Jones, NP
Peak, J
Brader, S
Eccles, SA
Katan, M [1 ]
机构
[1] Inst Canc Res, Canc Res UK Ctr Cell & Mol Biol, Chester Beatty Labs, London SW3 6JB, England
[2] Inst Canc Res, Canc Res UK Ctr Canc Therapeut, Sutton SM2 5NG, Surrey, England
关键词
PLC gamma 1; signalling; motility; extracellular matrix;
D O I
10.1242/jcs.02374
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 gamma 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 PLC gamma 1 to early, integrin-regulated changes leading to cell motility. The key role of PLC gamma 1 was supported by findings that specific depletion of PLC gamma 1 by small interfering (si)RNA, or by pharmacological inhibition, or the absence of this isoform in PLC gamma 1(-/-) cells resulted in the failure to form cell protrusions and undergo cell spreading and elongation in response to integrin engagement. This integrin-PLC gamma 1 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 PLC gamma 1 activity, beta 1 integrin and Src kinase are demonstrated to be essential for phosphorylation of PLC gamma 1, 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 beta 1 integrin or Src. Our findings establish PLC gamma 1 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 PLC gamma 1 in cell motility, functioning as a mediator of both growth factor and integrin-initiated signals.
引用
收藏
页码:2695 / 2706
页数:12
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