title: Asymmetrical macromolecular complex formation of lysophosphatidic acid receptor 2 (LPA2) mediates gradient sensing in fibroblasts.
abstract: Chemotactic migration of fibroblasts toward growth factors relies on their capacity to sense minute extracellular gradients and respond to spatially confined receptor-mediated signals. Currently, mechanisms underlying the gradient sensing of fibroblasts remain poorly understood. Using single-particle tracking methodology, we determined that a lysophosphatidic acid (LPA) gradient induces a spatiotemporally restricted decrease in the mobility of LPA receptor 2 (LPA2) on chemotactic fibroblasts. The onset of decreased LPA2 mobility correlates to the spatial recruitment and coupling to LPA2-interacting proteins that anchor the complex to the cytoskeleton. These localized PDZ motif-mediated macromolecular complexes of LPA2 trigger a Ca(2+) puff gradient that governs gradient sensing and directional migration in response to LPA. Disruption of the PDZ motif-mediated assembly of the macromolecular complex of LPA2 disorganizes the gradient of Ca(2+) puffs, disrupts gradient sensing, and reduces the directional migration of fibroblasts toward LPA. Our findings illustrate that the asymmetric macromolecular complex formation of chemoattractant receptors mediates gradient sensing and provides a new mechanistic basis for models to describe gradient sensing of fibroblasts.
authors.affiliation: From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Aixia
authors.initials: A
authors.lastname: Ren
authors.affiliation: From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, the Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Changsuk
authors.initials: C
authors.lastname: Moon
authors.affiliation: From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, the Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee 38103.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Chandrima
authors.initials: C
authors.lastname: Sinha
authors.affiliation: From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, the Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Yarlagadda
authors.affiliation: From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, the Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Kavisha
authors.initials: K
authors.lastname: Arora
authors.affiliation: the Department of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, and.
authors.forename: Xusheng
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Junming
authors.initials: J
authors.lastname: Yue
authors.affiliation: From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Parthasarathi
authors.affiliation: Olympus America Inc., Center Valley, Pennsylvania 18034.
authors.forename: Rick
authors.initials: R
authors.lastname: Heil-Chapdelaine
authors.affiliation: From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
authors.affiliation: From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, the Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, anaren@cchmc.org.
authors.forename: Anjaparavanda P
authors.initials: AP
authors.lastname: Naren
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002633:Chemotaxis; D005347:Fibroblasts / Q000502:physiology*; D008246:Lysophospholipids / Q000502:physiology; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D054799:Phospholipase C beta / Q000378:metabolism; D055503:Protein Multimerization; D021381:Protein Transport; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*
chemical_list: D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D054799:Phospholipase C beta; C032881:lysophosphatidic acid
keywords: Calcium Intracellular Release; Cell Migration; Cell Surface Receptor; Fibroblast; G Protein-coupled Receptor (GPCR); PDZ Domain