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A NOVEL INHIBITORY PATHWAY LINKING PROFILIN-1 AND BREAST CANCERCELL MOTILITY

Bae, Yong Ho (2010) A NOVEL INHIBITORY PATHWAY LINKING PROFILIN-1 AND BREAST CANCERCELL MOTILITY. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Profilin-1 (Pfn1 - a ubiquitously expressed actin-binding protein) levels are significantlydownregulated in various invasive adenocarcinomas including breast cancer. Although Pfn1 hasbeen shown to be required for motility for most normal cells, breast cancer cells and normalhuman mammary epithelial cells exhibit a hypermotile phenotype upon Pfn1 depletion, and reexpression of Pfn1 in breast cancer cells decreases their migration. The traditionally conceived pro-migratory function of Pfn1 through its relatively well-studied interactions with actin and polyproline ligands does not provide guidance to explain this context-specific effect of Pfn1 on cell migration. The overall goal of this study is to reveal molecular mechanisms underlying the hypermotile phenotype of breast cancer cells as a result of Pfn1 downregulation. We first show that loss of Pfn1 expression increases motility of breast cancer cells by enhancing targeting of Ena(enabled)/VASP (vasodilator stimulated phosphoprotein) family of actin-binding proteins to the leading edge, a feature that is also reproducible in other cells. We further demonstrate that Ena/VASP targeting to the leading edge is mediated through the action of lamellipodin (Lpd - a membrane anchoring protein) and Pfn1 negatively regulates membrane targeting of Lpd. Limiting Lpd expression impairs motility of Pfn1-deficient breast cancer cells, thereby demonstrating loss of Pfn1 augments breast cancer cell motility through enhanced membrane recruitment of VASP/Lpd complex. Subsequent rescue experiments with various ligand-binding deficient mutants of Pfn1, we further demonstrate that Pfn1 inhibits breast cancer cell motility mainly by its phosphoinositide interaction through negative regulation of Lpd/VASP targeting to the leading edge. Membrane targeting of Lpd in Pfn1-deficient breast cancer cells critically depends on the availability of D3-phosphorylated phosphoinositides, and consistent with this observation, we demonstrate that loss of Pfn1 expression significantly increases PI(3,4)P2 presentation at the leading edge. Collectively, these findings identify a novel inhibitory mechanism of Pfn1 on breast cancer cell motility by regulating membrane availability of PI(3,4)P2 and docking of Lpd, and this involves Pfn1¡¯s phosphoinositide interaction. This is in contrast to conventionally thought Pfn1¡¯s regulation of cell motility primarily through its interactions with actin and polyproline ligands.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Bae, Yong Hoyob1@pitt.eduYOB1
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRoy, Parthapar19@pitt.eduPAR19
Committee CoChairWells, Alanwellsa@upmc.eduAHW6
Committee MemberWu, Carycarywu@pitt.eduCARYWU
Committee MemberZeringue, Henryhcz1@pitt.eduHCZ1
Committee MemberDavidson, Lancelad43@pitt.eduLAD43
Date: 25 June 2010
Date Type: Completion
Defense Date: 6 November 2009
Approval Date: 25 June 2010
Submission Date: 31 March 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: breast cancer; cell motility; lamellipodin; phosphoinositide; Profilin-1; VASP
Other ID: http://etd.library.pitt.edu/ETD/available/etd-03312010-112610/, etd-03312010-112610
Date Deposited: 10 Nov 2011 19:33
Last Modified: 19 Dec 2016 14:35
URI: http://d-scholarship.pitt.edu/id/eprint/6677

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