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Inhibitor Levels Haemophilia

Microtubules are capable of bearing high external pressure and, thus, help to maintain the cells shape under physiological conditions. In migrating cells, the microtubule end points in the direction of the plasma membrane and microtubules reaching the leading edge grow, at least in epithelial cells, more persistent. Stabilization of growth can lead to a more persistent force transmission, even though the maximal pushing force decreases quadratically with length, due to buckling.Notably, the stabilization of microtubules does not only promote a more persistent microtubule growth, but also a steadier supply with material needed for migration, as these microtubules persist longer near the leading edge, being ideal tracks for material supply, in agreement with the preference of some kinesin motors for microtubules stabilized by acetylation and detyrosination. Consequently, the polymerization of microtubules can generate a force of a few piconewton, on the same order as the force generated by motor proteins. For a direct involvement of microtubules in the force generation process, a signicant amount of microtubules actually have to reach the cell front.In most cell types, only very few microtubules reach the lamellipodium and the generated force is insucient to generate large scale protrusions. In contrast, in neurons and astrocytes, microtubules are capable of generating protrusions.Notably, in axons these bundles point with their end away from the cell body, sucient to promote neurite outgrowth. Cell motion associated structures have a high material consumption and, therefore, a steady supply is necessary to allow a continuous movement.A further indirect way for microtubules to inuence cell motility is via the polymerization, as microtubules are associated with focal adhesions, and, consequently, actomyosin contractility. Furthermore, microtubules grow in the direction of existing focal adhesions at the cell front where they get entrapped and stabilized. Thereby, stress bers seem to function as a guidance structure for microtubules, mediated by MACF. A positive feedback loop is also possible where integrin stimulation could cause a favored delivery of cargo at the site of adhesion. A further possibility is an interaction of FAK or paxilin with APC that clusters at microtubule tips. Despite the adhesion favoring eect of microtubules, an opposing destabilizing eect was observed at the cell rear. Microtubules actively targeted mature focal adhesions at the rear of motile broblasts, accelerating focal adhesion turnover. A common model describes the phenomenon via the dynamic instability of microtubule laments.By growing and targeting focal adhesions, microtubules exert a force on the adhesion site, depolymerize quickly afterwards, and repeat the process. This hypothesis is supported by an Succimer observation showing a strong correlation between the microtubule poking number and the dissociation of focal adhesions. However, how microtubules nd and target focal adhesions is not yet fully understood.This idea is supported by the APC dependent localization of the spectraplakin MACF at the cell cortex, close to focal adhesions. Additionally, in the absence of MACF peripheral microtubules are less well organized and adhesion turnover is inhibited. Furthermore, the actin bundling protein Octocrilene fascin interacts with microtubules, promoting focal adhesion turnover via FAK. Nevertheless, the precise mechanism of action of intermediate laments is not fully elucidated.

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