RASSF4 controls SOCE and ER-PM junctions through regulation of PI(4,5)P2

J Cell Biol. 2017 Jul 3;216(7):2011-2025. doi: 10.1083/jcb.201606047. Epub 2017 Jun 9.

Abstract

RAS association domain family 4 (RASSF4) is involved in tumorigenesis and regulation of the Hippo pathway. In this study, we identify new functional roles of RASSF4. First, we discovered that RASSF4 regulates store-operated Ca2+ entry (SOCE), a fundamental Ca2+ signaling mechanism, by affecting the translocation of the endoplasmic reticulum (ER) Ca2+ sensor stromal interaction molecule 1 (STIM1) to ER-plasma membrane (PM) junctions. It was further revealed that RASSF4 regulates the formation of ER-PM junctions and the ER-PM tethering function of extended synaptotagmins E-Syt2 and E-Syt3. Moreover, steady-state PM phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2) levels, important for localization of STIM1 and E-Syts at ER-PM junctions, were reduced in RASSF4-knockdown cells. Furthermore, we demonstrated that RASSF4 interacts with and regulates the activity of adenosine diphosphate ribosylation factor 6 (ARF6), a small G protein and upstream regulator of type I phosphatidylinositol phosphate kinases (PIP5Ks) and PM PI(4,5)P2 levels. Overall, our study suggests that RASSF4 controls SOCE and ER-PM junctions through ARF6-dependent regulation of PM PI(4,5)P2 levels, pivotal for a variety of physiological processes.

Publication types

  • Video-Audio Media

MeSH terms

  • ADP-Ribosylation Factor 6
  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / metabolism
  • Calcium Signaling*
  • Cell Membrane / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Female
  • HeLa Cells
  • Humans
  • Microscopy, Fluorescence
  • Microscopy, Video
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • ORAI1 Protein / metabolism*
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Transport
  • RNA Interference
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism*
  • Synaptotagmin II / genetics
  • Synaptotagmin II / metabolism
  • Synaptotagmins / genetics
  • Synaptotagmins / metabolism
  • Time Factors
  • Time-Lapse Imaging
  • Transfection
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology

Substances

  • ADP-Ribosylation Factor 6
  • Neoplasm Proteins
  • ORAI1 Protein
  • ORAI1 protein, human
  • Phosphatidylinositol 4,5-Diphosphate
  • RASSF4 protein, human
  • STIM1 protein, human
  • SYT2 protein, human
  • SYT3 protein, human
  • Stromal Interaction Molecule 1
  • Synaptotagmin II
  • Tumor Suppressor Proteins
  • Synaptotagmins
  • Phosphotransferases (Alcohol Group Acceptor)
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • ADP-Ribosylation Factors
  • ARF6 protein, human

Associated data

  • RefSeq/NM_032023.3