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Actin-binding protein profilin1 is an important determinant of cellular phosphoinositide control.
Ricci, Morgan M C; Orenberg, Andrew; Ohayon, Lee; Gau, David; Wills, Rachel C; Bae, Yongho; Das, Tuhin; Koes, David; Hammond, Gerald R V; Roy, Partha.
Afiliación
  • Ricci MMC; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • Orenberg A; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • Ohayon L; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • Gau D; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • Wills RC; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • Bae Y; Department of Pathology and Anatomical Science, University at Buffalo, Buffalo, New York, USA.
  • Das T; Tavotek Biotherapeutics, Spring House, Pennsylvania, USA.
  • Koes D; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • Hammond GRV; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Electronic address: ghammond@pitt.edu.
  • Roy P; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Electronic address: par19@pitt.edu.
J Biol Chem ; 300(1): 105583, 2024 Jan.
Article en En | MEDLINE | ID: mdl-38141770
ABSTRACT
Membrane polyphosphoinositides (PPIs) are lipid-signaling molecules that undergo metabolic turnover and influence a diverse range of cellular functions. PPIs regulate the activity and/or spatial localization of a number of actin-binding proteins (ABPs) through direct interactions; however, it is much less clear whether ABPs could also be an integral part in regulating PPI signaling. In this study, we show that ABP profilin1 (Pfn1) is an important molecular determinant of the cellular content of PI(4,5)P2 (the most abundant PPI in cells). In growth factor (EGF) stimulation setting, Pfn1 depletion does not impact PI(4,5)P2 hydrolysis but enhances plasma membrane (PM) enrichment of PPIs that are produced downstream of activated PI3-kinase, including PI(3,4,5)P3 and PI(3,4)P2, the latter consistent with increased PM recruitment of SH2-containing inositol 5' phosphatase (SHIP2) (a key enzyme for PI(3,4)P2 biosynthesis). Although Pfn1 binds to PPIs in vitro, our data suggest that Pfn1's affinity to PPIs and PM presence in actual cells, if at all, is negligible, suggesting that Pfn1 is unlikely to directly compete with SHIP2 for binding to PM PPIs. Additionally, we provide evidence for Pfn1's interaction with SHIP2 in cells and modulation of this interaction upon EGF stimulation, raising an alternative possibility of Pfn1 binding as a potential restrictive mechanism for PM recruitment of SHIP2. In conclusion, our findings challenge the dogma of Pfn1's binding to PM by PPI interaction, uncover a previously unrecognized role of Pfn1 in PI(4,5)P2 homeostasis and provide a new mechanistic avenue of how an ABP could potentially impact PI3K signaling byproducts in cells through lipid phosphatase control.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfatidilinositoles / Profilinas Límite: Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfatidilinositoles / Profilinas Límite: Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos