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The PDZ adaptor protein, NHERF1, organizes and regulates protein complexes at the cell membrane

Wheeler, David S. (2010) The PDZ adaptor protein, NHERF1, organizes and regulates protein complexes at the cell membrane. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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G-protein coupled receptors (GPCRs) are the largest family of transmembrane proteins, constituting 2% of the human genome. They mediate signaling from a diverse set of ligands, ranging from photons to large peptides. Their intracellular signaling cascades are complex and highly malleable depending on cellular context. Yet, GPCR signaling in vivo is highly specific. Cells maintain this tight control over GPCR signaling through the expression of adaptor proteins. These adaptors regulate GPCR function and activation on many levels - they localize receptors to specific subcellular domains, assemble functional signaling complexes, alter the specificity of G-proteins coupling to the receptor, or regulate receptor traffic to and from the plasma membrane. By balancing the expression of these adaptor proteins, cells control where, when and how long GPCRs signal. Na+/H+ Exchanger Regulatory Factor 1 (NHERF1), also known as Ezrin binding phosphoprotein 50kDa (EBP50), is the prototypical PDZ adaptor protein. Expression of NHERF1 clusters parathyroid hormone type 1 receptor (PTH1R) and frizzled (Fzd) along actin stress fibers in non-polarized cells at the apical actin cap in polarized cells. In addition to proper localization, interaction with NHERF1 has several signaling manifestations. For PTH1R, interaction with NHERF1 can cause either a G-protein switch or can scaffold a PTH1R-PKA-calcium channel signaling complex. For Fzd, interaction with NHERF1 blocks Wnt-induced -catenin activation. NHERF1 knockout mice exhibit PTH-resistant phosphate excretion and enhanced PTH-induced vitamin D synthesis, as well as increased mammary duct density secondary to heightened Wnt-Fzd signaling. NHERF1 is a prime example of how PDZ adaptor proteins regulate GPCR localization and diversify GPCR signaling in physiologically significant ways.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Wheeler, David S.dsw10@pitt.eduDSW10
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeFranco, Donalddod1@pitt.eduDOD1
Committee MemberRomero, Guillermoggr@pitt.eduGGR
Committee MemberVilardaga, Jean-Pierrejpv@pitt.eduJPV
Committee MemberTraub, Linton Mtraub@pitt.eduTRAUB
Committee MemberFriedman, Peter Apaf10@pitt.eduPAF10
Date: 6 December 2010
Date Type: Completion
Defense Date: 18 November 2010
Approval Date: 6 December 2010
Submission Date: 2 December 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Frizzled; GPCR; NHERF1; PTH1R; adaptor protein; PDZ
Other ID:, etd-12022010-001029
Date Deposited: 10 Nov 2011 20:07
Last Modified: 15 Nov 2016 13:52


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