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Jamison, Joshua (2014) PROTEIN KINASE Cδ REGULATES THE RHYTHM OF CONTRACTILITY DURING GROWTH FACTOR INDUCED MIGRATION. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The skin is an important barrier essential for immune response. When the skin is wounded, the initial step of fibroblast migration into the tissue is required for subsequent restored and normal integrity of the skin. Fibroblasts involved in this process of wound healing require proper signaling critical for cell motility and contractions of the extracellular matrix (ECM). Furthermore, regeneration of dermal tissue represents one of the most intense anabolic processes, requiring a robust vascular system to deliver nutrients and remove dead debris. Endothelial cells are also influenced by the regulation of a provisional ECM by fibroblasts. As a reservoir of growth factors/cytokines for motility/regression, it functionally serves as a dynamic scaffold for vessels to graft into the wound to mediate angiogenesis. Both systems of angiogenesis and fibroblasts remodeling require growth factor induced regulation of motility. During growth factor induced motility, PLCy1 is activated via EGFR/VEGFR/other RTK signaling and produces diacylglycerol for coactivation of PKCδ to regulate MLC-2 contractility in fibroblast and endothelial cells. However, the functional regulation of PKCδ mediated contractile signaling has not been investigated fully, as it specifically relates to upstream signaling. Therefore, it is hypothesized PLCy1 dependent regulation of PKCδ mediates force signaling in these cell types. To test this hypothesis we first investigated the consequence of PKCδ translocation to the membrane for activation and whether localization is implicated in force regulation. To determine whether PKCδ activation during force signaling is mediated at the membrane, PKCδ was targeted to the membrane by engineering a K-ras farnesylation motif of the c-terminus of PKCδ. Membrane tethering of PKCδ led to increased directional force exertion onto the ECM/substrate, as upstream regulation is mediated by PLCy1. In addition, we also investigated, whether PKCδ regulation was involved in endothelial capillary retraction mediated by initial dissociation signals during wound healing. Endothelial cells were allowed to form cords on Matrigel, and cords were dissociated with CXCR3 ligand, CXCXL-4 (PF4). During this cord dissociation, we found that motile contractility mediated by VEGFR signaling is partially dependent on PKCδ. This study further supports PKCδ as a key regulator of contractility in cell migration.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Jamison, Joshuajaj64@pitt.eduJAJ64
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDefrances , Mariedefrancesmc@upmc.eduMCD14
Thesis AdvisorWells, Alanwellsa@upmc.eduAHW6
Committee MemberWu, Carycarywu@imap.pitt.eduCARYWU
Committee MemberHebda, Patricia A.hebda@pitt.eduHEBDA
Committee MemberWang, James H-C.wanghc@pitt.eduWANGHC
Date: 19 February 2014
Date Type: Publication
Defense Date: 10 December 2014
Approval Date: 19 February 2014
Submission Date: 18 February 2014
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 112
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: cell motility, cell migration, contractility, durotaxis, PKC-delta, growth factor, cell signaling,
Date Deposited: 19 Feb 2014 13:40
Last Modified: 19 Dec 2016 14:41


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