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PKA-Mediated Regulation of Profilin-1 - Implication in Sprouting Angiogenesis

Veon, III, William J. and Roy, Partha and Shroff, Sanjeev G. (2014) PKA-Mediated Regulation of Profilin-1 - Implication in Sprouting Angiogenesis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Angiogenesis is a process of vessel outgrowth from a pre-existing capillary that is implicated in many physiological and pathological conditions. Profilin-1 (Pfn1), a ubiquitously expressed actin-binding protein, has been previously shown to be up-regulated in vascular endothelial cells during capillary morphogenesis and required for endothelial cell migration, morphogenesis and invasion in vitro. In the first part of this study, we demonstrated that depletion of Pfn1 interferes with sprouting angiogenesis in vitro and ex vivo. In the second part, we further explored how Pfn1 might be biochemically regulated. Our studies suggested that a significant fraction of Pfn1 could exist in a number of phosphorylated states in cells. We showed that Pfn1 can be phosphorylated by Protein Kinase A (PKA) in vitro and in a PKA-dependent manner in vivo. By mass-spectrometry, we identified several potential PKA phosphorylation sites of Pfn1, one of which, T89, at least also appeared to be a bona fide modification site of Pfn1 in vivo. We performed biochemical and in silico analyses to determine the potential consequence of this phosphorylation on the properties of Pfn1. Finally, we showed that activating the PKA pathway affects ligand binding of Pfn1 in cells and negatively impacts both endothelial cell migration and sprouting angiogenesis. Collectively, these observations implicate a possible role for Pfn1 post-translational modification in the PKA-mediated regulation of sprouting angiogenesis.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Veon, III, William J.wjv3@pitt.eduWJV3
Roy, Parthapar19@pitt.eduPAR19
Shroff, Sanjeev G.sshroff@pitt.eduSSHROFF
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorRoy, Parthapar19@pitt.eduPAR19
Thesis AdvisorShroff, Sanjeev G.sshroff@pitt.eduSSHROFF
Committee MemberWells, Alanwellsa@msx.upmc.eduAHW6
Committee MemberHuard, Johnnyjhuard@pitt.eduJHUARD
Committee MemberStolz, Donna B.dstolz@pitt.eduDSTOLZ
Date: 19 September 2014
Date Type: Publication
Defense Date: 8 February 2014
Approval Date: 19 September 2014
Submission Date: 21 July 2014
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 143
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: Profilin; Profilin-1; Angiogenesis; Sprouting; Phosphorylation; Modification; Cytoskeleton; Actin
Date Deposited: 19 Sep 2014 18:35
Last Modified: 19 Sep 2019 05:15

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