Pak1 and PIX regulate contact inhibition during epithelial wound healing

Zegers, Mirjam M.; Forget, Marie-Annick; Chernoff, Jonathan; Mostov, Keith E.; Beest, Martin B.A. ter; Hansen, Steen Ingemann

doi:10.1093/emboj/cdg398

Cited by 69 publications

(88 citation statements)

References 49 publications

(76 reference statements)

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“…26 ARHGEF6, a cdc42 guanine exchange factor, mutated in human nonspecific mental retardation, interacts with paxillin, which is involved in cell proliferation, spreading and regulating contact inhibition through integrin-mediated cell signaling. 27 Its transcript and protein levels decrease twofold (Figures 3a and b) in Cbl cos -treated cells at 9 h of treatment compared with Cbl treatment alone. This reduced mRNA expression and protein level in Cbl cos cells may be essential for inhibition of tumorigenicity, such as cell proliferation and spreading, before apoptosis and may induce apoptosis as observed in other tumor cells.…”

Section: Resultsmentioning

confidence: 96%

“…It also modulates ROS production from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in a growth factor-dependent manner, 28 and downregulation of ARHGEF6 inhibits cell spreading and adhesion. 27 Reduction of expression in Cbl cos may act downstream of DNA repair signaling and help to signal cells to maintain excess ROS, to stop proliferation and further adhesion of cells. Physical interaction of DNA-PKc with ARHGEF6, implicating extensive DNA damage, may signal for cell-cycle inhibition, spreading and apoptosis regulation in Cbl cos -treated cells.…”

Section: Discussionmentioning

confidence: 99%

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Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Maiti

2009

Pharmacogenomics J

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Drug resistance in cancer cells involves complex molecular mechanisms and ovarian carcinoma cells become resistant to chlorambucil (Cbl) after continuous treatment. This drug-and ionizing radiation-resistant cells have lower level of endogenous ROS (reactive oxygen species) compared with sensitive cells. Elevation of the cellular ROS level by exogenous ROS generation increases the sensitivity of Cbl to resistant cells. In contrast, antioxidants prevent the sensitization of resistant cells to Cbl by H 2 O 2 , COS (chronic oxidative stress) or NOO À . The molecular mechanism of drug sensitivity with COS has been investigated by microarray gene expressions followed by gene network analysis and it reveals that a cdc42/rac1 guanine exchange factor, ARHGEF6, with p53 and DNA-Pkc (PRKDC) is central to induce apoptosis in Cbl cos (Cbl with COS) cells. mRNA and protein levels of major gene network pathway differ significantly in Cbl cos cells than in Cbltreated cells. Moreover, DNA-PKc physically interacts with ARHGEF6 and p53 mostly in the nucleus of Cbl-treated cells, whereas in Cbl cos -treated cells, its interactions are mostly in the cytoplasm. These results suggest that low doses of Cbl and very low doses of COS together kill Cbl-resistant ovarian carcinoma cells and ARHGEF6 signaling may have an instrumental role in induction of apoptosis in Cbl cos cells.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Maiti

2009

Pharmacogenomics J

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“…Sos has recently been shown to translocate to the plasma membrane in 293 cells in response to SLIT stimulation of the Robo receptor and by forming a complex with the receptor and the adaptor protein Dock (35). The Rac-GEF ␤PIX is involved in regulating contact inhibition by translocating from the cytosol to focal adhesion complexes in a way that depends on its interaction with and the kinase activity of PAK (36). A C-terminal coiled-coil domain of ␤PIX is also involved in its recruitment to the cell periphery and necessary for the formation of membrane ruffles and microvilli (37).…”

Section: Discussionmentioning

confidence: 99%

Membrane Translocation of P-Rex1 Is Mediated by G Protein βγ Subunits and Phosphoinositide 3-Kinase

Barber

Donald

Thelen

et al. 2007

Journal of Biological Chemistry

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P-Rex1 is a guanine-nucleotide exchange factor (GEF) for the small GTPase Rac that is directly activated by the ␤␥ subunits of heterotrimeric G proteins and by the lipid second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), which is generated by phosphoinositide 3-kinase (PI3K). G␤␥ subunits and PIP 3 are membrane-bound, whereas the intracellular localization of P-Rex1 in basal cells is cytosolic. Activation of PI3K alone is not sufficient to promote significant membrane translocation of P-Rex1. Here we investigated the subcellular localization of P-Rex1 by fractionation of Sf9 cells co-expressing P-Rex1 with G␤␥ and/or PI3K. In basal, serum-starved cells, P-Rex1 was mainly cytosolic, but 7% of the total was present in the 117,000 ؋ g membrane fraction. Co-expression of P-Rex1 with either G␤␥ or PI3K caused only an insignificant increase in P-Rex1 membrane localization, whereas G␤␥ and PI3K together synergistically caused a robust increase in membrane-localized P-Rex1 to 23% of the total. PI3K-driven P-Rex1 membrane recruitment was wortmannin-sensitive. The use of P-Rex1 mutants showed that the isolated Dbl homology/pleckstrin homology domain tandem of P-Rex1 is sufficient for synergistic G␤␥-and PI3K-driven membrane localization; that the enzymatic GEF activity of P-Rex1 is not required for membrane translocation; and that the other domains of P-Rex1 (DEP, PDZ, and IP4P) contribute to keeping the enzyme localized in the cytosol of basal cells. In vitro Rac2-GEF activity assays showed that membrane-derived purified P-Rex1 has a higher basal activity than cytosol-derived P-Rex1, but both can be further activated by PIP 3 and G␤␥ subunits.The small GTPase Rac (isoforms Rac1, Rac2, and Rac3) is a member of the Rho family of GTPases that regulates a range of important cellular functions, including gene expression, cytoskeletal structure, and reactive oxygen species formation (1). Like all small GTPases, Rac is directly activated by guaninenucleotide exchange factors (GEFs) 3 (2). The P-Rex family of Rac-GEFs is composed of P-Rex1, P-Rex2, and P-Rex2b (3-5). P-Rex1 is expressed in white blood cells and brain (3), P-Rex2 expression is more widespread but low or absent in leukocytes (4), and P-Rex2b, a splice variant of P-Rex2 that lacks the C-terminal half, is expressed mainly in the heart (5). Studies in P-Rex1-deficient mice have shown that P-Rex1 is involved in the regulation of G protein-coupled receptor (GPCR)-dependent Rac2 activation in neutrophils, production of reactive oxygen species, chemotaxis, and neutrophil recruitment to inflammatory sites (6, 7). In the neuronal PC12 cell line, RNA interference-mediated down-regulation of P-Rex1 leads to impaired neurotrophin-stimulated cell migration (8). In the endothelial HUVEC cell line, suppression of P-Rex2b levels by RNA interference results in reduced Rac1 activation and cell migration in response to sphingosine 1-phosphate (9). P-Rex family GEFs are directly and synergistically activated in vitro and in vivo by the ␤␥ subunits of heterotrimeric...

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“…For example, Cdc42 works upstream of Par6/aPKC and Cdc42-interacting protein 4 (CIP4), which control actin dynamics at the internalization site (Harris and Tepass 2010). Besides controlling the stability of cell-cell interactions, Rho GTPases, via PAK and bPIX, are reciprocally controlled by AJs in which they play an essential role on actin dynamics (Zegers et al 2003;Zegers and Friedl 2014). Interaction between cadherin -catenin clusters leads to the recruitment of the Rac guanine nucleotide exchange factor (GEF) TIAM1, which activates the Rho GTPase Rac1, and the activation of Rac1 in leader cells is, in turn, required for the formation of cell protrusions and traction forces observed at the edge of a cell cluster during collective cell migration (Hordijk et al 1997;Kovacs et al 2002;Mertens et al 2005).…”

Section: Cell-cell Adhesion Systemsmentioning

confidence: 99%

Tuning Collective Cell Migration by Cell–Cell Junction Regulation

Friedl

Mayor

2017

Cold Spring Harb Perspect Biol

294

253

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Collective cell migration critically depends on cell -cell interactions coupled to a dynamic actin cytoskeleton. Important cell-cell adhesion receptor systems implicated in controlling collective movements include cadherins, immunoglobulin superfamily members (L1CAM, NCAM, ALCAM), Ephrin/Eph receptors, Slit/Robo, connexins and integrins, and an adaptive array of intracellular adapter and signaling proteins. Depending on molecular composition and signaling context, cell -cell junctions adapt their shape and stability, and this gradual junction plasticity enables different types of collective cell movements such as epithelial sheet and cluster migration, branching morphogenesis and sprouting, collective network migration, as well as coordinated individual-cell migration and streaming. Thereby, plasticity of cell -cell junction composition and turnover defines the type of collective movements in epithelial, mesenchymal, neuronal, and immune cells, and defines migration coordination, anchorage, and cell dissociation. We here review cell -cell adhesion systems and their functions in different types of collective cell migration as key regulators of collective plasticity.

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Pak1 and PIX regulate contact inhibition during epithelial wound healing

Cited by 69 publications

References 49 publications

Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Membrane Translocation of P-Rex1 Is Mediated by G Protein βγ Subunits and Phosphoinositide 3-Kinase

Tuning Collective Cell Migration by Cell–Cell Junction Regulation

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