Slp2-a controls renal epithelial cell size through regulation of Rap-ezrin signaling independently of Rab27

Takao Yasuda, Mitsunori Fukuda

    Research output: Contribution to journalArticle

    6 Citations (Scopus)

    Abstract

    Synaptotagmin-like protein 2 (Slp2-a/Sytl2) is a Rab27 effector protein that regulates transport of Rab27-bearing vesicles and organelles through its N-terminal Rab27-binding domain and a phospholipid-binding C2A domain. Here we demonstrate a Rab27-independent function of Slp2-a in the control of renal cell size through a previously uncharacterized C2B domain. We found that by recruiting Rap1 GAPs to the plasma membrane of MDCK II cells through the C2B domain, Slp2-a inactivates Rap signaling and modulates the size of the cells. Functional ablation of Slp2-a resulted in an increase in the size of MDCK II cells. Drosophila Slp Bitesize was found to compensate for the function of Slp2-a in MDCK II cells, thereby indicating that the mechanism of the cell size control by Slp proteins has been evolutionarily conserved. Interestingly, blockade of the activity of ezrin, a downstream target of Rap, with the glucosylceramide synthase inhibitor, miglustat, effectively inhibited cell spreading of Slp2-a-knockdown cells. We also discovered aberrant expression of Slp2-a and increased activity of ezrin in pcy (Nphp3pcy) mice, a model of polycystic kidney disease that is characterized by renal cell spreading. Our findings indicate that Slp2-a controls renal cell size through regulation of Rap-ezrin signaling independently of Rab27.

    Original languageEnglish
    Pages (from-to)557-570
    Number of pages14
    JournalJournal of cell science
    Volume127
    Issue number3
    DOIs
    Publication statusPublished - 2014 Feb 1

    Keywords

    • Cell size
    • Ezrin
    • Polycystic kidney disease
    • Rap1GAP
    • Slp2-a

    ASJC Scopus subject areas

    • Cell Biology

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