Abstract
Activation of the enzyme phospholipase C (PLC) leads to the formation of second messengers inositol 1,4,5-trisphosphate and diacylglycerol. Tyrosine kinase receptors activate this reaction through PLCγ isoenzymes. PLCγ activity involves its activation with, and phosphorylation by, receptor tyrosine kinases. Recently, it has been shown that phosphoinositide 3-kinase (PI 3-K) may regulate PLCγ activity through the interaction of the PI 3-K product phosphatidylinositol 3,4,5-trisphosphate (PtdIns-3,4,5-P3) and the PLCγ pleckstrin homology (PH) domain. In an effort to understand the signalling pathway that involves PI 3-K regulation of PLCγ, we found that EGF induces a PI 3-K-dependent translocation of PLCγ1 at the leading edge of migrating cells in a wound healing assay. Similarly, the isolated PH, but not the Src-homology (SH) domains, N-SH2 or SH3, of PLCγ1, translocates at the leading edge. Our experiments also showed that stable PH PLCγ1 expression blocks epidermal growth factor (EGF)- and serum-induced cell motility and increases cell adhesion in MDA-MB-231 cells. This may suggest that influence of PI 3-K on PLCγ1 could be relevant in cell migration, where PLCγ1 seems to play a key role by modulating a series of events involved in actin polymerization.
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Acknowledgements
We would like to thank Prof P Innocenti and Prof G Fano for their support, Prof MA Horton for critical reading of the manuscript, Dr S-G Rhee and Dr M Katan for the gift of constructs. M Falasca is supported by an endowment from the Dr Mortimer and Mrs Theresa Sackler Trust. Publication (3) from the Sackler Institute for Muscular Skeletal Research, UCL. This work was supported in part by ‘Trenta ore per la vita’ and ‘Lega Italiana per la Lotta contro i Tumori’, Sezione di Pescara.
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Piccolo, E., Innominato, P., Mariggio, M. et al. The mechanism involved in the regulation of phospholipase Cγ1 activity in cell migration. Oncogene 21, 6520–6529 (2002). https://doi.org/10.1038/sj.onc.1205821
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DOI: https://doi.org/10.1038/sj.onc.1205821
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