uPAR Interaction and Regulation of Natural Killer Cell Integrins: Implications for the Modulation of NK Cell Migration and Invasion

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dc.contributor.advisorGoldfarb, Ronald H.
dc.contributor.committeeMemberRoque, Rouel
dc.contributor.committeeMemberHart, Mark
dc.creatorGellert, Ginelle C.
dc.date.accessioned2019-08-22T21:27:23Z
dc.date.available2019-08-22T21:27:23Z
dc.date.issued2003-05-01
dc.date.submitted2013-08-06T13:54:06-07:00
dc.description.abstractGellert, Ginelle C. uPAR Interaction and Regulation of Natural Killer Cell Integrins: Implications for the Modulation of NK Cell Migration and Invasion. Doctor of Philosophy (Biomedical Sciences), May 2003; pp. 118, 2 tables; 12 figures; bibliography 163. The urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored receptor, devoid of an intracellular domain, but nevertheless initiates signaling, possibly through lateral interactions with integrins. Since adoptively transferred interleuking-2 (IL-2) activated natural killer (A-NK) cells can accumulate within established cancer metastases, these A-NK cells may integrate components of adhesion and proteolysis to facilitate their infiltration into tumors. The work in this dissertation investigates the hypothesis that uPAR directly interacts with and regulates the expression of integrins on the surface of NK cells in the potential modulation of NK cell migration and invasion. Crosslinking studies have revealed a relationship between the integrins and uPAR on the surface of the human NK cell line, YT. Crosslinking uPAR, which mimics uPAR clustering at focal adhesion sites, caused an increase in the expression of the αM, αv and β2 integrins. Although uPAR is GPI-linked to the plasma membrane and has no direct means of initiating intracellular signaling, crosslinking uPAR activated the MEK/ERK signaling cascade, as phosphorylation of both MEK ½ and ERK ½ occurred following receptor clustering. The MEK-specific inhibitors PD98059 and U0126 blocked MAP kinase phosphorylation, and PD98059 inhibited the increase in integrin expression induced by uPAR crosslinking. Furthermore, the binding of urokinase plasminogen activator (uPA) to uPAR also activated the MEK/ERK signaling pathway. Fluorescence microscopy revealed the cocapping of uPAR with the αv integrin, a process inhibited N-acetyl-D-glucosamine, which abrogates the lectin-like interactions that have been suggested to exist between uPAR and integrins. The work presented herein indicated that signaling initiated either by uPAR crosslinking, leading to increased integrin surface expression, or by uPAR occupancy with uPA may depend on the physical association of uPAR with integrins. These studies will enhance our understanding of the mechanisms utilized by NK cells for their adhesion to tumor vasculature and accumulation within established cancer metastases, thereby potentially identifying targets for enhancing their effectiveness during adoptive immunotherapy.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/29346
dc.language.isoen
dc.provenance.legacyDownloads0
dc.subjectCancer Biology
dc.subjectCell Anatomy
dc.subjectCell and Developmental Biology
dc.subjectCell Biology
dc.subjectCells
dc.subjectCellular and Molecular Physiology
dc.subjectGenetics and Genomics
dc.subjectImmunity
dc.subjectImmunology and Infectious Disease
dc.subjectLife Sciences
dc.subjectMedical Cell Biology
dc.subjectMedical Immunology
dc.subjectMedical Molecular Biology
dc.subjectMedical Sciences
dc.subjectMedicine and Health Sciences
dc.subjectOther Cell and Developmental Biology
dc.subjectOther Immunology and Infectious Disease
dc.subjectRehabilitation and Therapy
dc.subjectNatural killer cells
dc.subjectintegrins
dc.subjectapoptotic cell death
dc.subjectintegrins
dc.subjectuPAR
dc.subjecttumor vasculature
dc.subjectcancer metastases
dc.subjectimmunotherapy
dc.titleuPAR Interaction and Regulation of Natural Killer Cell Integrins: Implications for the Modulation of NK Cell Migration and Invasion
dc.typeDissertation
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineBiomedical Sciences
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

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