The Sec14-like phosphatidylinositol transfer proteins Sec14l3/SEC14L2 act as GTPase proteins to mediate Wnt/Ca 2+ signaling

Elife. 2017 May 2;6:e26362. doi: 10.7554/eLife.26362.

Abstract

The non-canonical Wnt/Ca2+ signaling pathway plays important roles in embryonic development, tissue formation and diseases. However, it is unclear how the Wnt ligand-stimulated, G protein-coupled receptor Frizzled activates phospholipases for calcium release. Here, we report that the zebrafish/human phosphatidylinositol transfer protein Sec14l3/SEC14L2 act as GTPase proteins to transduce Wnt signals from Frizzled to phospholipase C (PLC). Depletion of sec14l3 attenuates Wnt/Ca2+ responsive activity and causes convergent and extension (CE) defects in zebrafish embryos. Biochemical analyses in mammalian cells indicate that Sec14l3-GDP forms complex with Frizzled and Dishevelled; Wnt ligand binding of Frizzled induces translocation of Sec14l3 to the plasma membrane; and then Sec14l3-GTP binds to and activates phospholipase Cδ4a (Plcδ4a); subsequently, Plcδ4a initiates phosphatidylinositol-4,5-bisphosphate (PIP2) signaling, ultimately stimulating calcium release. Furthermore, Plcδ4a can act as a GTPase-activating protein to accelerate the hydrolysis of Sec14l3-bound GTP to GDP. Our data provide a new insight into GTPase protein-coupled Wnt/Ca2+ signaling transduction.

Keywords: GTPase protein; Sec14l3/SEC14L2; Wnt/Ca2+; cell biology; cell movements; developmental biology; embryos; stem cells; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling*
  • Carrier Proteins / metabolism*
  • Cell Line
  • Frizzled Receptors / metabolism
  • GTP Phosphohydrolases / metabolism*
  • Humans
  • Lipoproteins / metabolism*
  • Phospholipid Transfer Proteins / metabolism*
  • Trans-Activators / metabolism*
  • Type C Phospholipases / metabolism
  • Wnt Signaling Pathway*
  • Zebrafish

Substances

  • Carrier Proteins
  • Frizzled Receptors
  • Lipoproteins
  • Phospholipid Transfer Proteins
  • SEC14L2 protein, human
  • SEC14L3 protein, human
  • Trans-Activators
  • Type C Phospholipases
  • GTP Phosphohydrolases

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.