Microenvironmental clues are critical to cell behavior. One of the key elements of migration is the generation and response to forces. Up to now, there is no definitive concept on how the generation and responses to cellular forces influence cancer-cell behavior. Here, we show that expression of receptor-type tyrosine-protein phosphatase alpha (RPTPa) in human SW480 colon cancer cells sets a threshold for the response to matrix forces by changing cellular contractility. This can be explained as an RPTPamediated increase in contractility with a consecutive increase in number and size of adhesion sites and stress fibers. These effects are mediated through myosin light chain kinase and largely independent of Rho/Rho-kinase (ROCK) signaling. In addition, we report that RPTPa influences spreading on low-rigidity surfaces, binding of collagen-coated beads and expression of RPTPa is required for invasion into the chorioallantoic membrane. These data suggest that force-responsive proteins such as RPTPa can influence cancer-cell behavior and identify potential targets for cancer therapy.

SummaryWe have analysed 11 human-specific Alu insertion polymorphisms in the Balkans to elucidate the origins of the Aromuns, a linguistic isolate inhabiting scattered areas in the Balkan Peninsula. Four Aromun samples (two from the Republic of Macedonia, one from Albania, and one from Romania) and five neighbouring populations (Macedonians, Albanians, Romanians, Greeks, and Turks) were analysed by means of genetic distances, principal components and analyses of the molecular variance (AMOVA). Three hypotheses were tested: Aromuns are Romanophonic Greeks; the result of a Romanian southward migration; or local descendants of the Thracians. The analyses show that the Aromuns do not constitute a homogeneous group separated from the rest of the Balkan populations. Grouping by language or geography does not explain the genetic differences observed in the region, suggesting a lack of genetic structure in the area. Aromuns do not seem to be particularly related to Greeks, Romanians, or to other Romance speakers. The Aromuns might have their origin to the south of the Danube river, with extensive gene flow with the neighbouring populations. The present results suggest a common ancestry of all Balkan populations, including Aromuns, with a lack of correlation between genetic differentiation and language or ethnicity, stressing that no major migration barriers have existed in the making of the complex Balkan human puzzle.

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Micro-environmental clues are critical to cell behavior. One of the key elements of migration is the generation and response to forces. Up to now there is no definitive concept on how the generation and responses to cellular forces influence cell behavior. Here, we show that phosphorylation of paxillin is a crucial event in the response to exogenous forces. Application of force induced growth of adhesion sites and this phenomenon was accompanied by a downregulation of Src family kinase activity, which in turn led to a decrease in the phosphorylation of paxillin at the tyrosine residues Y31 and Y118. The force-dependent growth of adhesion sites is mediated by a decrease in the turnover-rate of paxillin in focal contacts. This turnover critically depended on the phosphorylation state of paxillin at Y31/118. Paxillin is an important regulator in the control of the aggregate state of the whole adhesion site since the turnover of other adhesion site proteins such as vinculin is influenced by the phosphorylation state of paxillin as well. Taken together these data suggest that SFK dependent phosphorylation of paxillin is a crucial event in the regulation of adhesion site function in response to force.