A PtdInsP3- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity

Weiner, Orion D.; Neilsen, Paul O.; Prestwich, Glenn D.; Kirschner, Marc W.; Cantley, Lewis C.; Bourne, Henry R.

doi:10.1038/ncb811

Cited by 478 publications

(485 citation statements)

References 31 publications

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“…However, there is evidence that advocates against it: 1) overexpression of p120 does not affect the PI3K/Akt pathway ( Figure 7); 2) expression of ⌬N-p120 is able to inhibit Rac-dependent RhoA activation, suggesting that it influences GEF activity; 3) accumulation of RhoA-GTP induced by p120 is PI3K dependent. Therefore, the observed inhibition of phospho-Akt by ⌬N-p120 could be a consequence of ⌬N-p120 -promoted RhoA inhibition via a positive feedback loop involving PI3K and Rho GTPases (Bakin et al, 2000;Weiner et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Although modest at 20 min, there was full inhibition of the accumulation of phospho-Akt species at 120 min ( Figure 7A). These findings can be rationalized by postulating a positive feedback loop involving PI3K and Rho GTPases (Bakin et al, 2000;Weiner et al, 2002). Interestingly, no apparent inhibi- Figure 6.…”

Section: ⌬N-p120 Abrogates Activation Of Rhoa By Hgfmentioning

confidence: 99%

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p120 Catenin Is Required for Growth Factor–dependent Cell Motility and Scattering in Epithelial Cells

Cozzolino

Stagni

Spinardi

et al. 2003

MBoC

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Cadherin-mediated cell-cell adhesion is dynamically modulated during epithelial-mesenchymal transition triggered by activation of receptor tyrosine kinases (RTK) in epithelial cells. Several cadherin-binding proteins have been identified that control cell-cell adhesion. However, the mechanisms by which intercellular adhesion and cell motility are coregulated are still unknown. Here, we delineate a hitherto uncharted cooperation between RTKs, RhoA GTPase, and p120 catenin in instructing a motile behavior to epithelial cells. We found that expression of an N-terminus-deleted p120 catenin in a variety of epithelial cell types, including primary keratinocytes, effectively competes for endogenous p120 at cadherin binding sites and abrogates EGFstimulated cell motility as well as HGF-induced cell scattering. The deleted mutant also inhibits the PI3K-dependent RhoA activation ensuing receptor activation. Conversely, we also show that the ectopic expression of full-length p120 in epithelial cells promotes cytoskeletal changes, stimulates cell motility, and activates RhoA. Both motogenic response to p120 and RhoA activation require coactivation of signaling downstream of RTKs as they are suppressed by ablation of the Ras/PI3K pathway. These studies demonstrate that p120 catenin is a necessary target of RTKs in regulating cell motility and help define a novel pathway leading to RhoA activation, which may contribute to the early steps of metastatic invasion.

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Section: Discussionmentioning

confidence: 99%

Section: ⌬N-p120 Abrogates Activation Of Rhoa By Hgfmentioning

confidence: 99%

p120 Catenin Is Required for Growth Factor–dependent Cell Motility and Scattering in Epithelial Cells

Cozzolino

Stagni

Spinardi

et al. 2003

MBoC

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“…This suggests that it is through PI3-Kinase that R-Ras can regulate Rho activity to modulate cell migration. So far, PI3-Kinase has been shown to predominantly activate Rac or Cdc42 (Wang et al, 2002;Weiner et al, 2002;Srinivasan et al, 2003). PI3-Kinase can activate several molecules through specialized signaling motifs, including Dbl-homology (DH) domains (reviewed in Zheng, 2001).…”

Section: Discussionmentioning

confidence: 99%

R-Ras Controls Membrane Protrusion and Cell Migration through the Spatial Regulation of Rac and Rho

Wozniak

Kwong

Chodniewicz

et al. 2005

MBoC

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Although it is known that the spatial coordination of Rac and Rho activity is essential for cell migration, the molecular mechanisms regulating these GTPases during migration are unknown. We found that the expression of constitutively activated R-Ras (38V) blocked membrane protrusion and random migration. In contrast, expression of dominant negative R-Ras (41A) enhanced migrational persistence and membrane protrusion. Endogenous R-Ras is necessary for cell migration, as cells that were transfected with siRNA for R-Ras did not migrate. Expression of R-Ras (38V) decreased Rac activity and increased Rho activity around the entire cell periphery, whereas expression of dominant negative R-Ras (41A) showed the converse, suggesting that R-Ras can spatially activate Rho and inactivate Rac. Consistent with this role, endogenous R-Ras localized and was preferentially activated at the leading edge of migratory cells in response to adhesion. The effects of R-Ras on cell migration are mediated by PI3-Kinase, as an effector mutant that uncouples PI3-Kinase binding from R-Ras (38V) rescued migration. From these data, we hypothesize that R-Ras plays a key role in cell migration by locally regulating the switch from Rac to Rho activity after membrane protrusion and adhesion.

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“…However, we did observe that some cells expressing RACK1 completely lost the ability to migrate toward the chemoattractant (Supplementary Video 3-2). This may reflect higher levels of RACK1 expression in these cells, resulting in a more severe inhibition of PI3K activation and PIP 3 generation, thereby disrupting the positive feedback exerted by PIP 3 on PI3K activation, which has been shown to be required for the formation of persistent pseudopod and directed cell migration (Wang et al, 2002;Weiner et al, 2002). Interestingly, cells expressing BD1-2 showed chemotactic defects similar to those of RACK1-overexpressing cells, whereas cells expressing BD5-7 retained the wild-type-like chemotactic responses (Figure 10, D-F, and Supplementary Videos 4 and 5).…”

Section: Rack1 Regulates Chemotaxis Of Neutrophil-like Dhl60 Cellsmentioning

confidence: 99%

RACK1 Regulates Directional Cell Migration by Acting on Gβγ at the Interface with Its Effectors PLCβ and PI3Kγ

Chen

Lin

Shin

et al. 2008

MBoC

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Migration of cells up the chemoattractant gradients is mediated by the binding of chemoattractants to G protein-coupled receptors and activation of a network of coordinated excitatory and inhibitory signals. Although the excitatory process has been well studied, the molecular nature of the inhibitory signals remains largely elusive. Here we report that the receptor for activated C kinase 1 (RACK1), a novel binding protein of heterotrimeric G protein ␤␥ (G␤␥) subunits, acts as a negative regulator of directed cell migration. After chemoattractant-induced polarization of Jurkat and neutrophil-like differentiated HL60 (dHL60) cells, RACK1 interacts with G␤␥ and is recruited to the leading edge. Down-regulation of RACK1 dramatically enhances chemotaxis of cells, whereas overexpression of RACK1 or a fragment of RACK1 that retains G␤␥-binding capacity inhibits cell migration. Further studies reveal that RACK1 does not modulate cell migration through binding to other known interacting proteins such as PKC␤ and Src. Rather, RACK1 selectively inhibits G␤␥-stimulated phosphatidylinositol 3-kinase ␥ (PI3K␥) and phospholipase C (PLC) ␤ activity, due to the competitive binding of RACK1, PI3K␥, and PLC␤ to G␤␥. Taken together, these findings provide a novel mechanism of regulating cell migration, i.e., RACK1-mediated interference with G␤␥-dependent activation of key effectors critical for chemotaxis.

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A PtdInsP3- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity

Cited by 478 publications

References 31 publications

p120 Catenin Is Required for Growth Factor–dependent Cell Motility and Scattering in Epithelial Cells

p120 Catenin Is Required for Growth Factor–dependent Cell Motility and Scattering in Epithelial Cells

R-Ras Controls Membrane Protrusion and Cell Migration through the Spatial Regulation of Rac and Rho

RACK1 Regulates Directional Cell Migration by Acting on Gβγ at the Interface with Its Effectors PLCβ and PI3Kγ

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