scholarly journals Cancer-associated mutations in the protrusion-targeting region of p190RhoGAP impact tumor cell migration

2016 ◽  
Vol 214 (7) ◽  
pp. 859-873 ◽  
Author(s):  
Fabien Binamé ◽  
Aurélien Bidaud-Meynard ◽  
Laure Magnan ◽  
Léo Piquet ◽  
Bertille Montibus ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Leading Edge ◽  
Negative Regulator ◽  
Actin Binding ◽  
Tumor Cell Migration ◽  
Spatiotemporal Regulation ◽  
Localization Sequence ◽  
Actin Protrusions ◽  
And Function

Spatiotemporal regulation of RhoGTPases such as RhoA is required at the cell leading edge to achieve cell migration. p190RhoGAP (p190A) is the main negative regulator of RhoA and localizes to membrane protrusions, where its GTPase-activating protein (GAP) activity is required for directional migration. In this study, we investigated the molecular processes responsible for p190A targeting to actin protrusions. By analyzing the subcellular localization of truncated versions of p190A in hepatocellular carcinoma cells, we identified a novel functional p190A domain: the protrusion localization sequence (PLS) necessary and sufficient for p190A targeting to leading edges. Interestingly, the PLS is also required for the negative regulation of p190A RhoGAP activity. Further, we show that the F-actin binding protein cortactin binds the PLS and is required for p190A targeting to protrusions. Lastly, we demonstrate that cancer-associated mutations in PLS affect p190A localization and function, as well as tumor cell migration. Altogether, our data unveil a new mechanism of regulation of p190A in migrating tumor cells.

scholarly journals Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility

2006 ◽  
Vol 176 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Erik Sahai ◽  
Raquel Garcia-Medina ◽  
Jacques Pouysségur ◽  
Emmanuel Vial
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Rho Gtpases ◽  
Rho Kinase ◽  
Cell Movement ◽  
Leading Edge ◽  
Cell Periphery ◽  
Tumor Cell Migration ◽  
Tumor Cell Motility

Rho GTPases participate in various cellular processes, including normal and tumor cell migration. It has been reported that RhoA is targeted for degradation at the leading edge of migrating cells by the E3 ubiquitin ligase Smurf1, and that this is required for the formation of protrusions. We report that Smurf1-dependent RhoA degradation in tumor cells results in the down-regulation of Rho kinase (ROCK) activity and myosin light chain 2 (MLC2) phosphorylation at the cell periphery. The localized inhibition of contractile forces is necessary for the formation of lamellipodia and for tumor cell motility in 2D tissue culture assays. In 3D invasion assays, and in in vivo tumor cell migration, the inhibition of Smurf1 induces a mesenchymal–amoeboid–like transition that is associated with a more invasive phenotype. Our results suggest that Smurf1 is a pivotal regulator of tumor cell movement through its regulation of RhoA signaling.

scholarly journals Heat Shock Protein 27 Phosphorylation Regulates Tumor Cell Migration under Shear Stress

Biomolecules ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 50 ◽  
Author(s):  
Baohong Zhang ◽  
Fei Xie ◽  
Aziz Aziz ◽  
Shuai Shao ◽  
Wang Li ◽  
...  
Keyword(s):  
Shear Stress ◽  
Cell Migration ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Tumor Cell ◽  
Fluorescent Protein ◽  
Resonance Energy ◽  
Leading Edge ◽  
Heat Shock Protein 27 ◽  
Tumor Cell Migration

Heat shock protein 27 (HSP27) is a multifunctional protein that undergoes significant changes in its expression and phosphorylation in response to shear stress stimuli, suggesting that it may be involved in mechanotransduction. However, the mechanism of HSP27 affecting tumor cell migration under shear stress is still not clear. In this study, HSP27-enhanced cyan fluorescent protein (ECFP) and HSP27-Ypet plasmids are constructed to visualize the self-polymerization of HSP27 in living cells based on fluorescence resonance energy transfer technology. The results show that shear stress induces polar distribution of HSP27 to regulate the dynamic structure at the cell leading edge. Shear stress also promotes HSP27 depolymerization to small molecules and then regulates polar actin accumulation and focal adhesion kinase (FAK) polar activation, which further promotes tumor cell migration. This study suggests that HSP27 plays an important role in the regulation of shear stress-induced HeLa cell migration, and it also provides a theoretical basis for HSP27 as a potential drug target for metastasis.

scholarly journals Eosinophilic inflammation promotes CCL6-dependent metastatic tumor growth

2021 ◽  
Vol 7 (22) ◽  
pp. eabb5943
Author(s):  
Fei Li ◽  
Xufei Du ◽  
Fen Lan ◽  
Na Li ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Cell Migration ◽  
Bone Metastasis ◽  
Tumor Cell ◽  
Cancer Metastasis ◽  
Inflammatory Diseases ◽  
Metastatic Tumor ◽  
Eosinophil Infiltration ◽  
Tumor Cell Migration ◽  
Promote Tumor Cell ◽  
Chemokine Ligand

Compelling evidence suggests that inflammatory components contribute to cancer development. However, eosinophils, involved in several inflammatory diseases, were not fully explored in cancer metastasis. We show that airway inflammatory eosinophilia and colonic inflammation with eosinophil infiltration are both associated with increased metastasis in mice. Eosinophilia is responsible for increased bone metastasis in eosinophil-enriched Cd3δ-Il-5 transgenic (Il-5 Tg) mice. We also observe increased eosinophils in the malignant pleural effusion of cancer patients with pleural metastasis. Mechanistically, eosinophils promote tumor cell migration and metastasis formation through secreting C-C motif chemokine ligand 6 (CCL6). Genetic knockout of Ccl6 in Il-5 Tg mice remarkably attenuates bone metastasis. Moreover, inhibition of C-C chemokine receptor 1 (CCR1, the receptor of CCL6) in tumor cells reduces tumor cell migration and metastasis. Thus, our study identifies a CCL6-dependent prometastatic activity of eosinophils, which can be inhibited by targeting CCR1 and represent an approach to preventing metastatic disease.

scholarly journals Compensation mechanism in tumor cell migration

2003 ◽  
Vol 160 (2) ◽  
pp. 267-277 ◽  
Author(s):  
Katarina Wolf ◽  
Irina Mazo ◽  
Harry Leung ◽  
Katharina Engelke ◽  
Ulrich H. von Andrian ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Shape Change ◽  
Proteolytic Degradation ◽  
Amoeboid Movement ◽  
Tumor Cell Migration ◽  
Tumor Dissemination ◽  
Β1 Integrins

Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor–based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of β1 integrins and MT1–matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered β1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.

Sign in / Sign up

Export Citation Format

Share Document