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Title page for ETD etd-06222012-142651

Type of Document Dissertation
Author Cleghorn, Whitney Marie
URN etd-06222012-142651
Title Arrestins regulate cell spreading and motility via focal adhesion dynamics
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Brian E. Wadzinski Committee Chair
Alissa M. Weaver Committee Member
Heidi E. Hamm Committee Member
Roy Zent Committee Member
Vsevolod V. Gurevich Committee Member
  • structural biology
  • pharmacology
  • morphology
  • cell biology
  • GPCR
  • arrestin
Date of Defense 2012-06-08
Availability unrestricted
Arrestins bind G protein-coupled receptors and more than 100 non-receptor partners, regulating various signaling pathways and cellular functions. The interactions of many proteins (e.g., Src, JNK3, ERKĀ½, Mdm2, etc.) with receptor-bound arrestin localize these molecules to receptor-rich membranes. Our recent finding that arrestins bind microtubules and recruit signaling proteins to the cytoskeleton prompted us to investigate whether arrestins affect cell motility and morphology. Here we describe a novel function of arrestins, their direct effect on focal adhesion dynamics. We demonstrate excessive spreading of cells lacking both non-visual arrestins, which is substrate-independent, evident on both fibronectin and poly-D-lysine. Reduced activity of small GTPases RhoA and Rac1 in arrestin-deficient cells is only partially responsible for the cell spreading phenotype. Increased adhesion, reflected by elevated activity of focal adhesion proteins paxillin and focal adhesion kinase, underlies the exaggerated spreading of arrestin-null cells and their reduced motility. The absence of arrestins greatly increases the size and lifespan of focal adhesions, indicating that arrestins are necessary for rapid focal adhesion turnover. Focal adhesions in arrestin-deficient cells are insensitive to microtubules, suggesting that arrestins likely mediate the induction of focal adhesion disassembly upon microtubule regrowth. Overexpression of WT arrestins and their receptor binding-deficient mutants in arrestin-null cells rescues the phenotype, demonstrating that regulation of focal adhesion dynamics by arrestins is receptor-independent. This is the first demonstration that arrestins play a direct role in focal adhesion dynamics.
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