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Exploring Cellular Dynamics: From Vesicle Tethering to Cell Migration
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Forskargrupp Johan Kreuger)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cells in the body communicate with each other in order to cooperate efficiently. This communication is in part achieved by regulated secretion of signaling molecules, which when released from a cell may activate receptors present at the plasma membrane of an adjacent cell. Such signals affect both cell fate and behavior. Dysregulated signaling may lead to disease, including cancer. This thesis is focused on how exocytosis and subsequent activation and trafficking of receptors can be regulated, and what the consequences of this regulation may be for cell migration.

Actin filaments are important transport structures for secretory vesicle trafficking. In Paper 1, actin polymerization was shown to induce formation of ordered lipid domains in the plasma membrane. Accordingly, actin filaments may thus create and stabilize specific membrane domains that enable docking of vesicles containing secretory cargo.

The RhoGEF FGD5 regulates Cdc42 which can result in cytoskeletal rearrangements. In Paper II, FGD5 was shown to be selectively expressed in blood vessels and required for normal VEGFR2 signaling. FGD5 protected VEGFR2 from proteasome-mediated degradation and was essential for endothelial cells to efficiently respond to chemotactic gradients of VEGFA.

The exocyst component EXOC7 is essential for tethering secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. In Paper III, EXOC7 was required for trafficking of VEGFR2-containing vesicles to the inner plasma membrane and VEGFR2 presentation at the cell surface.

The ability of tumor cells to escape the primary tumor and establish metastasis is in part dependent on their capacity to migrate. In Paper IV, a method based on time-lapse microscopy and fluorescent dyes was created to analyze single cancer cell migration in mixed cancer cell cultures, and in particular the influence of different types on neighboring cells was assessed.

In conclusion, these studies have enhanced our understanding of the mechanisms behind cellular trafficking, and may be applied in the future to develop more specific therapeutics to treat cancer and other diseases associated with abnormal angiogenesis and cellular migration.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 46 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1282
Keyword [en]
angiogenesis, cancer, cell migration, exocyst complex, exocytosis, FGD5, lipid rafts, plasma membrane, receptor trafficking, VEGFR2
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-306174ISBN: 978-91-554-9768-2OAI: oai:DiVA.org:uu-306174DiVA: diva2:1039982
Public defence
2016-12-15, B22, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2016-11-24 Created: 2016-10-25 Last updated: 2016-11-29
List of papers
1. Actin filaments attachment at the plasma membrane in live cells cause the formation of ordered lipid domains
Open this publication in new window or tab >>Actin filaments attachment at the plasma membrane in live cells cause the formation of ordered lipid domains
2013 (English)In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1828, no 3, 1102-1111 p.Article in journal (Refereed) Published
Abstract [en]

The relationship between ordered plasma membrane nanodomains, known as lipid rafts, and actin filaments is the focus of this study. Plasma membrane order was followed in live cells at 37°C using laurdan and di-4-ANEPPDHQ to report on lipid packing. Disrupting actin polymerisation decreased the fraction of ordered domains, which strongly argue that unstimulated cells have a basal level of ordered domains. Stabilising actin filaments had the opposite effect and increased the proportion of ordered domains. Decreasing the plasma membrane level of 4-phosphate-inositides lowers the number of attachment points for actin filaments and reduced the proportion of ordered domains. Aggregation of plasma membrane molecules, both lipid raft and non-lipid raft markers, lead to the formation of ordered domains. The increase in ordered domains was correlated with an increase in actin filaments just beneath the plasma membrane. In live cell plasma membrane blebs, which are detached from the underlying actin filaments, the fraction of ordered domains was low and GM1 could not be patched to form ordered domains. We conclude that ordered domains form when actin filaments attach to the plasma membrane. This downplays lipid-lipid interactions as the main driving force behind the formation of ordered membrane domains in vivo, giving greater prominence to membrane-intracellular filament interactions.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-196480 (URN)10.1016/j.bbamem.2012.12.004 (DOI)000315473400021 ()23246974 (PubMedID)
Available from: 2013-03-10 Created: 2013-03-10 Last updated: 2016-10-28Bibliographically approved
2. FGD5 sustains vascular endothelial growth factor A (VEGFA) Signaling through inhibition of proteasome-mediated VEGF-receptor 2 degradation
Open this publication in new window or tab >>FGD5 sustains vascular endothelial growth factor A (VEGFA) Signaling through inhibition of proteasome-mediated VEGF-receptor 2 degradation
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-306177 (URN)
Available from: 2016-10-25 Created: 2016-10-25 Last updated: 2016-10-28
3. Exocyst complex component 7 (EXOC7) regulates vascular endothelial growth factor receptor 2 (VEGFR2) trafficking to the plasma membrane
Open this publication in new window or tab >>Exocyst complex component 7 (EXOC7) regulates vascular endothelial growth factor receptor 2 (VEGFR2) trafficking to the plasma membrane
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-306178 (URN)
Available from: 2016-10-25 Created: 2016-10-25 Last updated: 2016-10-28
4. A tracking strategy for analyzing single cancer cell migration behavior in mixed cancer cell cultures
Open this publication in new window or tab >>A tracking strategy for analyzing single cancer cell migration behavior in mixed cancer cell cultures
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-306561 (URN)
Available from: 2016-10-28 Created: 2016-10-28 Last updated: 2016-10-28

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Ashrafzadeh, Parham
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