title: Protein phosphatase-2A restricts migration of Lewis lung carcinoma cells by modulating the phosphorylation of focal adhesion proteins.
abstract: Compared to metastatic Lewis lung carcinoma (LLC) cells, nonmetastatic LLC cells have increased levels of activity of the protein phosphatase PP-2A, which functions to limit their migration through transwell chambers. Inhibition of PP-2A in nonmetastatic LLC stimulates their transmigration to levels similar to those of metastatic LLC cells. Studies to define the signaling pathways intermediate between diminished PP-2A activity and stimulated migration showed that inhibiting PP-2A activity resulted in paxillin serine hyperphosphorylation and tyrosine dephosphorylation. Paxillin was important for the stimulated migration because the increased transmigration in response to PP-2A inhibition was dampened by expression of mutant paxillin at the LIM3 S457 and S481 residues. Inhibition of PP-2A also led to the dissolution of FAK/Src/paxillin focal adhesion complexes, which was also dependent on paxillin S457 and S481 residues. In addition, inhibition of PP-2A resulted in dephosphorylation of Src inhibitory Y527 residue, suggesting increased Src activity. The stimulated transmigration of cells with diminished PP-2A was in part dependent on this Src activity. These studies show the importance of PP-2A in limiting tumor cell migration through its modulation of proteins of the focal adhesions.
authors.affiliation: Research Service, Edward Hines, Jr. VA Hospital, Hines, IL 60141, USA.
authors.forename: M Rita I
authors.initials: MR
authors.lastname: Young
authors.forename: Shirley W
authors.initials: SW
authors.lastname: Liu
authors.forename: Jeremy
authors.initials: J
authors.lastname: Meisinger
mesh_terms: D000818:Animals; D001717:Birds; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000201:enzymology* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D022001:Focal Adhesions / Q000187:drug effects / Q000502:physiology; D016391:Genes, src / Q000502:physiology*; D006801:Humans; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D051419:Paxillin; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011233:Precipitin Tests; D054648:Protein Phosphatase 2; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; C496062:Pxn protein, mouse; D010768:Phosphoserine; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2