Sylvie Lachmann

London Research Institute, Londinium, England, United Kingdom

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Publications (2)9.41 Total impact

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    ABSTRACT: Aberrant signalling of receptor tyrosine kinases (RTKs), such as c-Met, the receptor for hepatocyte growth factor (HGF), has been implicated in the oncogenesis of various tumours including non-small cell lung carcinoma (NSCLC). Through its pro-migratory properties, c-Met has been implicated specifically in the process of tumour metastasis demanding a better understanding of the underlying signalling pathways. Various players downstream of c-Met have been well characterised, including the extracellular-signal-regulated kinases (ERKs) 1/2. In a small interfering (si) RNA based high throughput wound healing screen performed in A549 lung carcinoma cells, we identified ERK2 but not ERK1 as a strong mediator of HGF-induced motility. This finding was confirmed in several NSCLC cell lines as well as HeLa cells. One known substrate for ERK kinases in cell migration, the focal adhesion protein paxillin, was also one of the hits identified in the screen. We demonstrate that HGF stimulation results in a time dependent phosphorylation of paxillin on serine 126, a process which can be blocked by inhibition of the ERK1/2 upstream kinase Mitogen-Activated Protein Kinase/ERK Kinase 1 (MEK1) or inhibition of glycogen synthase kinase (GSK) 3. Further we show that paxillin turnover at focal adhesions is increased upon HGF-stimulation, an effect that is dependent on serines 126 (GSK3 site) and 130 (ERK site) within paxillin. In line with the isoform specific requirement of ERK2 for HGF-mediated migration in lung tumour cell models, ERK2 but not ERK1 is shown to be responsible for paxillin S126 phosphorylation and its increased turnover at focal adhesions.
    Journal of Cell Science 04/2013; · 5.88 Impact Factor
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    ABSTRACT: The mammalian protein kinase N (PKN) family of Serine/Threonine kinases comprises three isoforms, which are targets for Rho family GTPases. Small GTPases are major regulators of the cellular cytoskeleton, generating interest in the role(s) of specific PKN isoforms in processes such as cell migration and invasion. It has been reported that PKN3 is required for prostate tumour cell invasion but not PKN1 or 2. Here we employ a cell model, the 5637 bladder tumour cell line where PKN2 is relatively highly expressed, to assess the potential redundancy of these isoforms in migratory responses. It is established that PKN2 has a critical role in the migration and invasion of these cells. Furthermore, using a PKN wild-type and chimera rescue strategy, it is shown that PKN isoforms are not simply redundant in supporting migration, but appear to be linked through isoform specific regulatory domain properties to selective upstream signals. It is concluded that intervention in PKNs may need to be directed at multiple isoforms to be effective in different cell types.
    PLoS ONE 01/2011; 6(7):e21732. · 3.53 Impact Factor