title: Inhibition of HSP27 phosphorylation by a cell-permeant MAPKAP Kinase 2 inhibitor.
abstract: Heat shock protein 27 (HSP27) has been implicated in many intracellular signaling processes. Since the phosphorylation of HSP27 can modulate its activity, the ability to inhibit phosphorylation of HSP27 might have clinical relevance especially with regard to the treatment of fibrosis. We have developed a cell-permeant peptide inhibitor of MAPKAP Kinase 2 (MK2), an enzyme that phosphorylates HSP27, by combining a previously described peptide substrate of MK2 with a cell penetrating peptide. This novel MK2 inhibitor (MK2i) reduced HSP27 phosphorylation by MK2 in vitro. At 10 microM, MK2i inhibited TGF-beta1-induced HSP27 phosphorylation in serum-starved human keloid fibroblasts. In addition, 10 microM MK2i decreased TGF-beta1-induced expression of connective tissue growth factor and collagen type I within serum-starved keloid fibroblasts. Thus, MK2i represents a potential therapeutic for the treatment of fibrotic disorders.
authors.affiliation: Albany College of Pharmacy and Health Sciences, Albany, NY 12208, USA.
authors.forename: Luciana B
authors.initials: LB
authors.lastname: Lopes
authors.forename: Charles
authors.initials: C
authors.lastname: Flynn
authors.forename: Padmini
authors.initials: P
authors.lastname: Komalavilas
authors.forename: Alyssa
authors.initials: A
authors.lastname: Panitch
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Brophy
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Seal
mesh_terms: D000595:Amino Acid Sequence; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D055551:HSP27 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D053773:Transforming Growth Factor beta1; D000099190:MAP-Kinase-Activated Kinase 2; C540575:MK2i peptide