title: The phosphatidylinositol-transfer protein Nir2 binds phosphatidic acid and positively regulates phosphoinositide signalling.
abstract: Phosphatidic acid (PA) and phosphoinositides are metabolically interconverted lipid second messengers that have central roles in many growth factor (GF)-stimulated signalling pathways. Yet, little is known about the mechanisms that coordinate their production and downstream signalling. Here we show that the phosphatidylinositol (PI)-transfer protein Nir2 translocates from the Golgi complex to the plasma membrane in response to GF stimulation. This translocation is triggered by PA formation and is mediated by its C-terminal region that binds PA in vitro. We further show that depletion of Nir2 substantially reduces the PI(4,5)P2 levels at the plasma membrane and concomitantly GF-stimulated PI(3,4,5)P3 production. Finally, we show that Nir2 positively regulates the MAPK and PI3K/AKT pathways. We propose that Nir2 through its PA-binding capability and PI-transfer activity can couple PA to phosphoinositide signalling, and possibly coordinates their local lipid metabolism and downstream signalling.
authors.affiliation: Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: SoHui
authors.initials: S
authors.lastname: Kim
authors.forename: Amir
authors.initials: A
authors.lastname: Kedan
authors.forename: Merav
authors.initials: M
authors.lastname: Marom
authors.forename: Nancy
authors.initials: N
authors.lastname: Gavert
authors.forename: Omer
authors.initials: O
authors.lastname: Keinan
authors.forename: Michael
authors.initials: M
authors.lastname: Selitrennik
authors.forename: Orly
authors.initials: O
authors.lastname: Laufman
authors.forename: Sima
authors.initials: S
authors.lastname: Lev
mesh_terms: D000595:Amino Acid Sequence; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010712:Phosphatidic Acids / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; D005136:Eye Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C113505:PITPNM1 protein, human; D010712:Phosphatidic Acids; D010716:Phosphatidylinositols; D019869:Phosphatidylinositol 3-Kinases
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