title: The PDZ protein GIPC regulates trafficking of the LPA1 receptor from APPL signaling endosomes and attenuates the cell's response to LPA.
abstract: Lysophosphatidic acid (LPA) mediates diverse cellular responses through the activation of at least six LPA receptors--LPA(1-6,) but the interacting proteins and signaling pathways that mediate the specificity of these receptors are largely unknown. We noticed that LPA(1) contains a PDZ binding motif (SVV) identical to that present in two other proteins that interact with the PDZ protein GIPC. GIPC is involved in endocytic trafficking of several receptors including TrkA, VEGFR2, lutropin and dopamine D2 receptors. Here we show that GIPC binds directly to the PDZ binding motif of LPA(1) but not that of other LPA receptors. LPA(1) colocalizes and coimmunoprecipitates with GIPC and its binding partner APPL, an activator of Akt signaling found on APPL signaling endosomes. GIPC depletion by siRNA disturbed trafficking of LPA(1) to EEA1 early endosomes and promoted LPA(1) mediated Akt signaling, cell proliferation, and cell motility. We propose that GIPC binds LPA(1) and promotes its trafficking from APPL-containing signaling endosomes to EEA1 early endosomes and thus attenuates LPA-mediated Akt signaling from APPL endosomes.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Tal
authors.initials: T
authors.lastname: Varsano
authors.forename: Vanessa
authors.initials: V
authors.lastname: Taupin
authors.forename: Lixia
authors.initials: L
authors.lastname: Guo
authors.forename: Oscar Y
authors.initials: OY
authors.lastname: Baterina
authors.forename: Marilyn G
authors.initials: MG
authors.lastname: Farquhar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D020816:Amino Acid Motifs; D001665:Binding Sites; D002465:Cell Movement; D049109:Cell Proliferation; D011992:Endosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C492009:GIPC1 protein, human; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D051057:Proto-Oncogene Proteins c-akt; C032881:lysophosphatidic acid