Understanding microtubule dynamics for improved cancer therapy

Abstract

Microtubules (MTs), key components of the cytoskeleton, are dynamic polymers of tubulin that form a well-organized network of polarized tube filaments. MT dynamics are highly regulated both spacially and temporally by several MT-related proteins, themselves regulated by several kinases and phosphatases via signaling cascades, and also by coordinated interactions with actin cytoskeleton and adhesion sites. Regulation of MT dynamics is crucial for mitosis, cell migration, cell signaling and trafficking. MT-targeted drugs (MTDs), which constitute a major anticancer drug family with antimitotic and antiangiogenic properties, inhibit tumor progression mainly by altering MT dynamics in both cancer and endothelial cells. Identification of proteins regulating the MT network will lead to a better understanding of tumor progression regulators and will be helpful in improving cancer therapy.

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

“…Migratory cells form a stable sub-population of microtubules at the leading edge to reorient the microtubule organizing center (MTOC) between the nucleus and the leading edge to create a polarized microtubule array that directs vesicular trafficking and maintains cell shape [9,10,19]. Additionally, disruption of the microtubule network by nocodazole-induced microtubule catastrophe or taxol-mediated microtubule stabilization, results in a depolarized cell morphology and a dramatic reduction in both the rate and directionality of migration [2,20].…”

“…Additionally, disruption of the microtubule network by nocodazole-induced microtubule catastrophe or taxol-mediated microtubule stabilization, results in a depolarized cell morphology and a dramatic reduction in both the rate and directionality of migration [2,20]. Conversely, release from the stabilizing effects of microtubule antagonists has been shown to induce microtubule regrowth toward the membrane ruffle, activation of Rac1 and the formation of filopodia and lamellipodia [2,19,21]. lamellipodia, ruffles, filopodia and lamellae.…”

“…However at the trailing edge, the dynamic instability of microtubules regulates the maintenance or dissolution of focal adhesions [19,21,34]. For example, nocodazole-induced microtubule depolymerisation leads to an increase in the number and size of focal adhesions at both the leading and trailing edge, anchoring the cell to the ECM to the point where it becomes immobilized [19].…”

“…However at the trailing edge, the dynamic instability of microtubules regulates the maintenance or dissolution of focal adhesions [19,21,34]. For example, nocodazole-induced microtubule depolymerisation leads to an increase in the number and size of focal adhesions at both the leading and trailing edge, anchoring the cell to the ECM to the point where it becomes immobilized [19]. Rescue of microtubule growth following catastrophe shows a resurgence in targeting events of focal adhesions by microtubule plus ends, resulting in focal adhesion dissolution and cell migration [2,19,20].…”

“…For example, nocodazole-induced microtubule depolymerisation leads to an increase in the number and size of focal adhesions at both the leading and trailing edge, anchoring the cell to the ECM to the point where it becomes immobilized [19]. Rescue of microtubule growth following catastrophe shows a resurgence in targeting events of focal adhesions by microtubule plus ends, resulting in focal adhesion dissolution and cell migration [2,19,20]. Microtubule plus ends have been shown to be differentially regulated depending on their subcellular location within the migrating cell.…”