title: Actin-regulated feedback loop based on Phactr4, PP1 and cofilin maintains the actin monomer pool.
abstract: Phactr proteins bind actin and protein phosphatase 1 (PP1), and are involved in processes ranging from angiogenesis to cell cycle regulation. Phactrs share a highly conserved RPEL domain with the myocardin-related transcription factor (MRTF) family, where actin binding to this domain regulates both the nuclear localization and the activity of these transcription coactivators. We show here that in contrast to MRTF-A, the RPEL domain is dispensable for the subcellular localization of Phactr4. Instead, we find the domain facilitating competitive binding of monomeric actin and PP1 to Phactr4. Binding of actin to Phactr4 influences the activity of PP1 and the phosphorylation status of one of its downstream targets, cofilin. Consequently, at low actin monomer levels, Phactr4 guides PP1 to dephosphorylate cofilin. This active form of cofilin is then able to sever and depolymerize actin filaments and thus restore the actin monomer pool. Accordingly, our data discloses the central role of Phactr4 in a feedback loop, where actin monomers regulate their own number via the activation of a key regulator of actin dynamics. Depending on the protein context, the RPEL domain can thus elicit mechanistically different responses to maintain the cellular actin balance.
authors.affiliation: Program in Cell and Molecular Biology, Institute of Biotechnology, University of Helsinki, 00014 Finland, 00014 Finland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Huet
authors.forename: Eeva Kaisa
authors.initials: EK
authors.lastname: Rajakylä
authors.forename: Tiina
authors.initials: T
authors.lastname: Viita
authors.forename: Kari-Pekka
authors.initials: KP
authors.lastname: Skarp
authors.forename: Marko
authors.initials: M
authors.lastname: Crivaro
authors.forename: Joseph
authors.initials: J
authors.lastname: Dopie
authors.forename: Maria K
authors.initials: MK
authors.lastname: Vartiainen
mesh_terms: D000199:Actins / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D051338:Cofilin 1 / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000378:metabolism*
chemical_list: D000199:Actins; D051338:Cofilin 1; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; C522018:Phactr4 protein, mouse; D054645:Protein Phosphatase 1