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Essential Role of Protein Phosphatase-1 in Mitogenic Signaling and Breast Cancer

机译:蛋白磷酸酶-1在有丝分裂信号和乳腺癌中的重要作用

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Organization of the actin cytoskeleton is crucial for a diverse set of cell functions including cell division, intracellular signaling, cell shape, and motility. Cancerous cells demonstrate changes in cell adhesion and growth consistent with altered regulation of the actin cytoskeleton. Our research has focused on the regulation of protein phosphorylation, specifically signals mediated by protein phosphatase 1 (PP 1), a serinelthreonine phosphatase, in these processes. Current work is focused on a class of regulatory subunits, neurabin I and neurabin II, that direct PPl to the actin cytoskeleton. Neurabin I and neurabin II were cloned from rat tissue either as PP1 or F-actin binding proteins and contain multiple domains. We have cloned homologs of these proteins from Xenopus laevis and C. elegans. The high degree of structural homology from worms to mammals in specific domains, such as the PPl binding domain and PDZ domain, begin to highlight regions most likely to be important for the in vivo function of these proteins in these diverse species. GFP-tagged neurabins were expressed in several mammalian cells and established the requirement for an N- terminal actin- binding domain in the localization of neurabins to the actin cytoskeleton. Expression of UFP-neurabin I lacking C-terminal sequences, which include a SAM (sterile alpha motif) and coiled-coil domains, caused cells to develop extensive surface projections or filopodia. Substitution of the KIKF460 sequence, which represents a PP1-binding site conserved in many PPl regulators, with alanines abolished PP1 binding and the mutant GFP-neurabin I while still localizing to the actin cytoskeleton failed to induce filopodia. The ability of GFP-neurabin I to induce filopodia was also inhibited by treatment of cells with the cell-permeable phosphatase inhibitors, okadaic acid or calyculin A, at concentrations that suppressed PP1 activity.

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