|Cell Polarity and Migration - CNRS URA2592|
|HEAD||Dr ETIENNE-MANNEVILLE Sandrine / firstname.lastname@example.org|
|MEMBERS||Dr CAMAND Emeline / Dr MZALI Rym / OSMANI Naël / VALLOIS Isabelle
Our research focuses on the control cell polarization and migration. We use primary rat astrocytes and astrocyte derived tumors to develop in vitro models of cell migration and polarization. In these systems, we investigate the role (i) of cell adhesion to the extracellular matrix and integrin signaling (ii) of homologue and heterologue cell-cell contacts and cadherin signaling (iii) and of different tumor suppressors (APC, LKB1, PTEN, Dlg, Scrib).
i) In a scratch-induced migration assay, integrins are activated at the wound edge of the cells (Etienne-Manneville et al., Cell, 2001). Integrin activation is one of the first events leading to cell polarization and migration via a signaling pathway involving the small GTPase Cdc42 (Etienne-Manneville et al., 2003; Manneville et al., 2005). We have shown that Scrib, the mammalian orthologue of the Drosophila tumor suppressor and polarity protein Scribble, is involved in astrocyte polarization (Osmani et al., 2006; see figure). Scrib is recruited in an integrin-dependent manner to the leading edge of migrating astrocytes where it binds to the Cdc42 exchange factor βPIX. Localization of Scrib and further association with βPIX induce Cdc42 activation and recruitment to the leading edge. Scrib thereby promotes polarization of both microtubule and actin cytoskeletons, centrosome and Golgi apparatus reorientation and directed cell migration.
ii) N-cadherin based adherens junctions are the main type of cell-cell junctions in astrocytes. Using RNA interference, we show that N-cadherin is involved in directed cell migration by modulating the integrin signaling pathway that controls cell polarization. Our ongoing work focuses on the molecular mechanisms by which N-cadherin modulates Scrib-Cdc42 polarity pathway. We also use adhesive micropatterns to study intrinsic cell polarization in three configurations: single isolated astrocytes, group of astrocytes interacting via N-cadherin adherens junctions or astrocytes interacting with a second cell type that does not express N-cadherin.
iii) LKB1 is a serine/threonine kinase involved in Peutz-Jegher syndrome. It is also the closest homologue of the C. elegans polarity protein PAR-4. We have shown that LKB1 was required for centrosome reorientation during astrocyte migration and that both its catalytic and its carboxy-terminal domains are essential for this function (Forcet et al., 2005). We now aim at characterizing the regulatory mechanisms and the downstream targets of LKB1 during cell polarization.
Our results extend our knowledge of polarity signaling pathways and their regulation in migrating cells. They also further confirm the functional conservation of several polarity proteins such as Scrib, N-cadherin or LKB1.
|Publications 2006 of the unit on Pasteur's references database|
Activity Reports 2006 - Institut Pasteur
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