Tumor cells exhibit two different modes of individual cell movement. Mesenchymal-type movement is characterized by an elongated cellular morphology and requires extracellular proteolysis. In amoeboid movement, cells have a rounded morphology, are less dependent on proteases, and require high Rho-kinase signaling to drive elevated levels of actomyosin contractility. These two modes of cell movement are interconvertible. We show that mesenchymal-type movement in melanoma cells is driven by activation of the GTPase Rac through a complex containing NEDD9, a recently identified melanoma metastasis gene, and DOCK3, a Rac guanine nucleotide exchange factor. Rac signals through WAVE2 to direct mesenchymal movement and suppress amoeboid movement through decreasing actomyosin contractility. Conversely, in amoeboid movement, Rho-kinase signaling activates a Rac GAP, ARHGAP22, that suppresses mesenchymal movement by inactivating Rac. We demonstrate tight interplay between Rho and Rac in determining different modes of tumor cell movement, revealing how tumor cells switch between different modes of movement.
The interactions of protein kinases and phosphatases with their regulatory subunits and substrates underpin cellular regulation. We identified a kinase and phosphatase interaction (KPI) network of 1844 interactions in budding yeast by mass spectrometric analysis of protein complexes. The KPI network contained many dense local regions of interactions that suggested new functions. Notably, the cell cycle phosphatase Cdc14 associated with multiple kinases that revealed roles for Cdc14 in mitogen-activated protein kinase signaling, the DNA damage response, and metabolism, whereas interactions of the target of rapamycin complex 1 (TORC1) uncovered new effector kinases in nitrogen and carbon metabolism. An extensive backbone of kinase-kinase interactions cross-connects the proteome and may serve to coordinate diverse cellular responses.
SummaryNeural precursor expressed, developmentally down-regulated 9 (NEDD9), a member of the Cas family of signal transduction molecules, is amplified at the genetic level in melanoma, and elevated expression levels have been shown to correlate with melanoma progression and metastasis. NEDD9 interacts with the guanine nucleotide exchange factor DOCK3 to promote Rac activation and the elongated, mesenchymal-type of tumour cell invasion, but the molecular mechanisms through which NEDD9 promotes melanoma metastasis are not fully understood. We show that signalling through increased NEDD9 levels requires integrin b3 signalling, which leads to elevated phosphorylation of integrin b3. This results in increased Src and FAK but decreased ROCK signalling to drive elongated, mesenchymaltype invasion in environments that contain vitronectin. NEDD9 overexpression does not affect ROCK signalling through activation of RhoA but decreases ROCKII signalling through Src-dependent phosphorylation of a negative regulatory site Tyr722. In NEDD9-overexpressing melanoma cells, inhibition of Src with dasatinib results in a switch from Rac-driven elongated, mesenchymal-type invasion to ROCK-dependent rounded, amoeboid invasion. These findings brings into question whether dasatinib would work as a therapeutic agent to block melanoma invasion and metastasis. On the basis of the in vitro data presented here, a combination treatment of dasatinib and a ROCK inhibitor might be a better alternative in order to inhibit both elongated, mesenchymal-type and rounded, amoeboid motility.
Background: β-catenin and transforming growth factor β signaling are activated in fibroblasts during wound healing. Both signaling pathways positively regulate fibroblast proliferation during this reparative process, and the effect of transforming growth factor β is partially mediated by β-catenin. Other cellular processes, such as cell motility and the induction of extracellular matrix contraction, also play important roles during wound repair. We examined the function of β-catenin and its interaction with transforming growth factor β in cell motility and the induction of collagen lattice contraction.
Objectives: The average person living in North America is exposed to hundreds of chemical ingredients, including those that are harmful to human health, through application of personal care products. The manufacture of personal care products is largely untested and unregulated at a government level; legislation is not as prescriptive as the public would expect it to be. This shifts the responsibility to consumers to use their own discretion when purchasing personal care products. The purpose of this research was to assess the knowledge of the Canadian general public regarding ingredients in personal care products to determine if they have enough knowledge to avoid harmful substances. Methods: A knowledge assessment survey was conducted to two different groups in Canada. The first group consisted of the general public who did not have a background in toxicology or dermatology, and the second group consisted of Public Health Inspectors in Lower Mainland B.C. The test scores from the knowledge assessment were compared between the two groups to determine if there was a significant difference in the means. Results: The survey was completed by 39 Public Health Inspectors and 91 members of the general public. The mean score was 3.0256 for the Public Health Inspectors and 1.846 for the general public; the test score was out of 10. Statistical analyses showed that the mean test scores were significantly different and the null hypothesis (Ho: mean test score of the Public Health Inspectors = mean test score of the general public) was rejected at α= 0.05. Conclusion: The result showed that both groups had low level of knowledge regarding the ingredients in personal care products that are widely used in Canada. Even the chemical ingredients that are known or suspected to be dangerous to human health or have adverse effects on the environment were not recognized. Exposure to potentially hazardous chemicals can be prevented or reduced by setting a legal requirement of a maximum concentration, imposing marketing restrictions or requiring better labelling of hazardous ingredients to improve public awareness of potential risk.
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