The regulation of cellular trafficking of the human lysophosphatidic acid receptor 1: identification of the molecular determinants required for receptor trafficking

dc.contributor.advisor Merrill, Alfred H.
dc.contributor.advisor Radhakrishna, Harish
dc.contributor.author Urs, Nikhil Mahabir en_US
dc.contributor.committeeMember Kowalczyk, Andrew
dc.contributor.committeeMember McCarty, Nael
dc.contributor.committeeMember Sewer, Marion
dc.contributor.department Biology en_US
dc.date.accessioned 2007-08-16T17:42:52Z
dc.date.available 2007-08-16T17:42:52Z
dc.date.issued 2007-05-16 en_US
dc.description.abstract The following thesis research was undertaken to gain a better understanding of the mechanisms that regulate the cellular trafficking and signaling of the endothelial differentiation gene (EDG) family of G-protein coupled receptors, LPA1, LPA2, and LPA3. This thesis will specifically focus on the regulation of the trafficking of the LPA1 Lysophosphatidic acid receptor, which is the most widely expressed and has been shown to be a major regulator of migration of cells expressing it. The initial studies undertaken in this project were aimed at understanding the endocytic pathway followed by the LPA1 receptor. Lysophosphatidic acid (LPA), an abundant serum phospholipid, stimulates heterotrimeric G protein signaling by activating three closely related receptors, termed LPA1, LPA2 and LPA3. In the first part of the project we show that in addition to promoting LPA1 signaling, membrane cholesterol is essential for the association of LPA1 with β-arrestin, which leads to signal attenuation and clathrin dependent endocytosis of LPA1. The second phase of the project was aimed at elucidating the different structural motifs required for the trafficking and signaling of the LPA1 receptor and helping us gain a more mechanistic view of the processes involved in its regulation. In the second part of the project we show that agonist-independent internalization of the LPA1 receptor is clathrin adaptor, AP-2 dependent and PKC-dependent and that it requires a distal dileucine motif, whereas agonist-dependent internalization of the LPA1 receptor is β-arrestin and clathrin-dependent and requires a cluster of serine residues in the tail region, which is upstream of the dileucine motif. These studies collectively vastly enhance our understanding of mechanisms that regulate LPA1 trafficking and signaling. These studies can also be applied to other G-protein coupled receptors making the task easier for other scientists to understand this vast family of receptors. en_US
dc.description.degree Ph.D. en_US
dc.identifier.uri http://hdl.handle.net/1853/16177
dc.publisher Georgia Institute of Technology en_US
dc.subject Motifs en_US
dc.subject Cholesterol en_US
dc.subject PKC en_US
dc.subject LPA1 en_US
dc.subject LPA en_US
dc.subject Beta-Arrestin en_US
dc.subject Trafficking en_US
dc.subject GPCR en_US
dc.subject.lcsh Cell interaction en_US
dc.subject.lcsh Lysophospholipids en_US
dc.title The regulation of cellular trafficking of the human lysophosphatidic acid receptor 1: identification of the molecular determinants required for receptor trafficking en_US
dc.type Text
dc.type.genre Dissertation
dspace.entity.type Publication
local.contributor.advisor Merrill, Alfred H.
local.contributor.corporatename College of Sciences
local.contributor.corporatename School of Biological Sciences
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relation.isOrgUnitOfPublication c8b3bd08-9989-40d3-afe3-e0ad8d5c72b5
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