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The large GTPase Dynamin 2 (Dyn2) is known to increase the invasiveness of pancreatic cancer tumor cells, but the mechanisms by which Dyn2 regulates changes in the actin cytoskeleton to drive cell migration are still unclear. Here we report that a direct interaction between Dyn2 and the actin bundling protein alpha-actinin (α-actinin) 4 is critical for tumor cell migration and remodeling of the extracellular matrix in pancreatic ductal adenocarcinoma (PDAC) cells. The direct interaction is mediated through the C-terminal tails of both Dyn2 and α-actinin 4, and these proteins interact at invasive structures at the plasma membrane. While Dyn2 binds directly to both α-actinin 1 and α-actinin 4, only the interaction with α-actinin 4 is required to promote tumor cell invasion. Specific disruption of the Dyn2 - α-actinin 4 interaction blocks the ability of PDAC cells to migrate in either 2-dimensions or invade through extracellular matrix as a result of impaired invadopodia stability. Analysis of human PDAC tumor tissue additionally reveals that elevated α-actinin 4 or Dyn2 expression are predictive of poor survival. Overall, these data demonstrate that Dyn2 regulates cytoskeletal dynamics, in part, by interacting with the actin binding protein α-actinin 4 during tumor cell invasion. [Media: see text] [Media: see text].
This article was published in the following journal.
Name: Molecular biology of the cell
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Serum glycoprotein produced by activated MACROPHAGES and other mammalian MONONUCLEAR LEUKOCYTES. It has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. Also known as TNF-alpha, it is only 30% homologous to TNF-beta (LYMPHOTOXIN), but they share TNF RECEPTORS.
A subtype of dynamin found primarily in the NEURONS of the brain.
A subtype of dynamin found ubiquitously expressed in a variety of tissues.
A subtype of dynamin found expressed exclusively in the testis, lung and brain.
A TCF transcription factor that was originally identified as a DNA-binding protein that interacts with the enhancers of T-CELL RECEPTOR ALPHA GENES. It is a plays a role in T-LYMPHOCYTE development.
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