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The Actin Filament System: Its Involvement in Cell Migration and Neurotransmitter Release
Stockholm University, Faculty of Science, The Wenner-Gren Institute . (Department of Cell Biology)
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The microfilament system consists of actin filaments as the major component and is regulated by a number of actin binding proteins. It is juxtaposed to the plasma membrane where it forms a dense cortical weave from where it pervades into the cell interior. This filament system has multiple roles and participates in virtually all motile processes where its dynamic activities depend on receptor mediated signaling leading to constant polymerizations and depolymerizations. These activities are now also known to affect gene regulation. This thesis discusses these dynamic reorganizations of the microfilament system and how components are supplied to support these motile processes. The focus is on profilin/profilin:actin, actin polymerization and the localization of the transcripts of these proteins.

The localization of profilin mRNA was examined in relation to the distribution of β-actin mRNA using fluorescent in situ hybridization. It was concluded that both these mRNAs localize to sites of massive actin polymerization called dorsal ruffles albeit the data obtained suggests that this localization must be dependent on distinct mechanisms. Additionally signal transduction and cell motility was studied after depleting the two profilin isoforms 1 and 2. The activity of the transcription factor SRF is known to be coupled to microfilament system dynamics via the cofactor MAL which binds to actin monomers and is released upon receptor mediated actin polymerization. Depletion of profilin was seen to influence SRF dependent signaling, most likely because the lack of profilin enables more MAL to bind actin monomers thereby preventing SRF dependent transcription. Finally, it was also investigated how the synaptic vesicle protein synaptotagmin 1 which is involved in exocytosis, has a role in actin polymerization. This protein has previously been described to cause filopodia formation when ectopically expressed. A polybasic sequence motif was identified as the effector sequence for this activity and it was established that this sequence interacts with anionic lipids. It is also discussed how this sequence could have a role in neurotransmitter release and actin polymerization in the nerve synapse.

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University , 2011. , 122 p.
Keyword [en]
Actin, Profilin, Synaptotagmin
National Category
Cell Biology
Research subject
Cell Biology
Identifiers
URN: urn:nbn:se:su:diva-56877ISBN: 978-91-7447-292-9OAI: oai:DiVA.org:su-56877DiVA: diva2:413557
Public defence
2011-05-31, sal E306, Arrheniuslaboratorierna, Svante Arrhenius 20 C, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Submitted. Available from: 2011-05-09 Created: 2011-04-28 Last updated: 2011-12-14Bibliographically approved
List of papers
1. Microtubule-dependent localization of profilin I mRNA to actin polymerization sites in serum-stimulated cells
Open this publication in new window or tab >>Microtubule-dependent localization of profilin I mRNA to actin polymerization sites in serum-stimulated cells
2010 (English)In: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 89, no 5, 394-401 p.Article in journal (Refereed) Published
Abstract [en]

Specific localization of messenger RNA (mRNA) appears to be a general mechanism to accumulate certain proteins to subcellular compartments for participation in local processes, thereby maintaining cell polarity under strict spatiotemporal control. Transportation of mRNA with associated protein components (RNP granules) by the actin microfilament or the microtubule systems is one important mechanism to achieve this locally distributed protein production. Here we provide evidence for a microtubule-dependent localization of mRNA encoding the actin regulatory protein profilin to sites in mouse embryonic fibroblasts, which express enhanced actin polymerization.

Keyword
Actin polymerization, Profilin, mRNA localization, FISH, microtubules
National Category
Cell and Molecular Biology
Research subject
Cellbiology
Identifiers
urn:nbn:se:su:diva-56880 (URN)10.1016/j.ejcb.2009.10.020 (DOI)
Available from: 2011-04-29 Created: 2011-04-28 Last updated: 2011-05-07Bibliographically approved
2. Profilin I and II are both influencing SRF-dependent signaling in B16 melanoma cells and loss of Profilin I interferes with cell migration
Open this publication in new window or tab >>Profilin I and II are both influencing SRF-dependent signaling in B16 melanoma cells and loss of Profilin I interferes with cell migration
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Profilin is a central component of the microfilament system. Its involvement in controlling actin polymerization associated with transmembrane signaling through its interaction with phosphatidylinositol lipids and a plethora of protein components carrying proline-rich sequence motifs has inspired to a large number of studies. Despite these efforts, however, its function is still not well understood. Therefore we have initiated a study of cultured cells after down-regulation of profilin expression using siRNA. Here we report that depletion of the profilin I and II isoforms in B16 mouse melanoma cells interferes with MAL/SRF-dependent transcription and that loss of profilin reduces their speed of migration as well as their ability to fine-tune their control of the migratory apparatus.

National Category
Cell Biology
Research subject
Cellbiology
Identifiers
urn:nbn:se:su:diva-57369 (URN)
Available from: 2011-05-07 Created: 2011-05-07 Last updated: 2011-05-07Bibliographically approved
3. Synaptotagmin 1 causes phosphatidyl inositol lipid-dependent actin remodeling in cultured non-neuronal and neuronal cells
Open this publication in new window or tab >>Synaptotagmin 1 causes phosphatidyl inositol lipid-dependent actin remodeling in cultured non-neuronal and neuronal cells
2012 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 318, no 2, 114-126 p.Article in journal (Refereed) Published
Abstract [en]

Here we demonstrate that a dramatic actin polymerizing activity caused by ectopic expression of the synaptic vesicle protein synaptotagmin 1 that results in extensive filopodia formation is due to the presence of a lysine rich sequence motif immediately at the cytoplasmic side of the transmembrane domain of the protein. This polybasic sequence interacts with anionic phospholipids in vitro, and, consequently, the actin remodeling caused by this sequence is interfered with by expression of a phosphatidyl inositol (4,5)-bisphosphate (PIP2)-targeted phosphatase, suggesting that it intervenes with the function of PIP2-binding actin control proteins. The activity drastically alters the behavior of a range of cultured cells including the neuroblastoma cell line SH-SY5Y and primary cortical mouse neurons, and, since the sequence is conserved also in synaptotagmin 2, it may reflect an important fine-tuning role for these two proteins during synaptic vesicle fusion and neurotransmitter release.

National Category
Cell Biology
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-65644 (URN)10.1016/j.yexcr.2011.10.009 (DOI)000297902800003 ()22036579 (PubMedID)
Available from: 2011-12-13 Created: 2011-12-13 Last updated: 2012-05-31Bibliographically approved

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