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Non-catalytic role of phosphoinositide 3-kinase in mesenchymal cell migration through non-canonical induction of p85β/AP2-mediated endocytosis

Author

Listed:
  • Hideaki T. Matsubayashi

    (Johns Hopkins University
    Johns Hopkins University
    Tohoku University)

  • Jack Mountain

    (Johns Hopkins University
    Johns Hopkins University)

  • Nozomi Takahashi

    (Tohoku University)

  • Abhijit Deb Roy

    (Johns Hopkins University
    Johns Hopkins University)

  • Tony Yao

    (Johns Hopkins University
    Johns Hopkins University)

  • Amy F. Peterson

    (Johns Hopkins University
    Johns Hopkins University)

  • Cristian Saez Gonzalez

    (Johns Hopkins University
    Johns Hopkins University)

  • Ibuki Kawamata

    (Tohoku University
    Ochanomizu University
    Kyoto University)

  • Takanari Inoue

    (Johns Hopkins University
    Johns Hopkins University)

Abstract

Class IA phosphoinositide 3-kinase (PI3K) galvanizes fundamental cellular processes such as migration, proliferation, and differentiation. To enable these multifaceted roles, the catalytic subunit p110 utilizes the multi-domain, regulatory subunit p85 through its inter SH2 domain (iSH2). In cell migration, its product PI(3,4,5)P3 generates locomotive activity. While non-catalytic roles are also implicated, underlying mechanisms and their relationship to PI(3,4,5)P3 signaling remain elusive. Here, we report that a disordered region of iSH2 contains AP2 binding motifs which can trigger clathrin and dynamin-mediated endocytosis independent of PI3K catalytic activity. The AP2 binding motif mutants of p85 aberrantly accumulate at focal adhesions and increase both velocity and persistency in fibroblast migration. We thus propose the dual functionality of PI3K in the control of cell motility, catalytic and non-catalytic, arising distinctly from juxtaposed regions within iSH2.

Suggested Citation

  • Hideaki T. Matsubayashi & Jack Mountain & Nozomi Takahashi & Abhijit Deb Roy & Tony Yao & Amy F. Peterson & Cristian Saez Gonzalez & Ibuki Kawamata & Takanari Inoue, 2024. "Non-catalytic role of phosphoinositide 3-kinase in mesenchymal cell migration through non-canonical induction of p85β/AP2-mediated endocytosis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46855-y
    DOI: 10.1038/s41467-024-46855-y
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    References listed on IDEAS

    as
    1. Emmanuel Boucrot & Antonio P. A. Ferreira & Leonardo Almeida-Souza & Sylvain Debard & Yvonne Vallis & Gillian Howard & Laetitia Bertot & Nathalie Sauvonnet & Harvey T. McMahon, 2015. "Endophilin marks and controls a clathrin-independent endocytic pathway," Nature, Nature, vol. 517(7535), pages 460-465, January.
    2. Abhijit Deb Roy & Taofei Yin & Shilpa Choudhary & Vladimir Rodionov & Carol C. Pilbeam & Yi I. Wu, 2017. "Optogenetic activation of Plexin-B1 reveals contact repulsion between osteoclasts and osteoblasts," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
    3. Bernard T. Kelly & Airlie J. McCoy & Kira Späte & Sharon E. Miller & Philip R. Evans & Stefan Höning & David J. Owen, 2008. "A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex," Nature, Nature, vol. 456(7224), pages 976-979, December.
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