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Spatio-temporal Rho GTPase signaling mechanisms during cell migration

English title Spatio-temporal Rho GTPase signaling mechanisms during cell migration
Applicant Pertz Olivier
Number 139201
Funding scheme SNSF Professorships
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Cellular Biology, Cytology
Start/End 01.12.2011 - 30.11.2013
Approved amount 759'500.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Molecular Biology

Keywords (5)

cytoskeleton; FRET biosensors; Signaling; Microfluidics; cell migration

Lay Summary (English)

Lead
Lay summary

The present project proposes to study how a cell reads extracellular cues and translate them in intracellular information to produce directional movement. This ability of vertebrate cells to directionally migrate is critical to development, the immune response and wound healing, and its regulation is compromised in pathologies such as metastatic cancer and vascular disease. By example during wound healing, cells use an internal “compass” to orient themeselves and move in the direction of the wound for the healing process. The same machinery also enables cancer cells to orient and move towards blood vessels, where they will enter the blood circulation, allowing the spread of the disease. This depends on very complex “signaling” mechanisms, in which the compass translates extracellular cues into intracellular information that will dynamically reorganize the cell’s skeleton to orient “the mechanical forces” that enable cell movement. Understanding the precise molecular signaling mechanisms how the compass senses extracellular cues, and how it relays information to the cell’s skeleton is thus crucial to find targets that could affect any of the processes described above. In the context of wound healing or the immune response, this could lead to the design of anti-inflammatory drugs, whereas in the context of cancer, it could target the metastatic spread of the disease which is the most devastating step in cancer.

 

In our precedent working period, we have set up a number of technologies that allow us to study signaling during cell migration with unprecedented resolution in time and in space. This takes advantage of microfabrication techniques to mimic the native environment that migrating cells encounter in vivo, allowing for robust induction of cell motility. This also takes advantage of “biosensors”, that allow to visualize signaling in space and in time in single living cells. We are now using these tools to characterize the spatio-temporal signaling profiles in two distinct prototypical cell migration modes that take advantage of different cytoskeleton and adhesion dynamics. This might allow to target specifically migrating cells in a number of different pathologies.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Spatio-temporal co-ordination of RhoA, Rac1 and Cdc42 activation during prototypical edge protrusion and retraction dynamics.
Martin Katrin, Reimann Andreas, Fritz Rafael D, Ryu Hyunryul, Jeon Noo Li, Pertz Olivier (2016), Spatio-temporal co-ordination of RhoA, Rac1 and Cdc42 activation during prototypical edge protrusion and retraction dynamics., in Scientific reports, 6, 21901-21901.
The dynamics of spatio-temporal Rho GTPase signaling: formation of signaling patterns.
Fritz Rafael Dominik, Pertz Olivier (2016), The dynamics of spatio-temporal Rho GTPase signaling: formation of signaling patterns., in F1000Research, 5, 1-3.
Growth Cone Localization of the mRNA Encoding the Chromatin Regulator HMGN5 Modulates Neurite Outgrowth.
Moretti Francesca, Rolando Chiara, Winker Moritz, Ivanek Robert, Rodriguez Javier, Von Kriegsheim Alex, Taylor Verdon, Bustin Michael, Pertz Olivier (2015), Growth Cone Localization of the mRNA Encoding the Chromatin Regulator HMGN5 Modulates Neurite Outgrowth., in Molecular and cellular biology, 35(11), 2035-50.
SrGAP2-Dependent Integration of Membrane Geometry and Slit-Robo-Repulsive Cues Regulates Fibroblast Contact Inhibition of Locomotion.
Fritz Rafael Dominik, Menshykau Denis, Martin Katrin, Reimann Andreas, Pontelli Valeria, Pertz Olivier (2015), SrGAP2-Dependent Integration of Membrane Geometry and Slit-Robo-Repulsive Cues Regulates Fibroblast Contact Inhibition of Locomotion., in Developmental cell, 35(1), 78-92.
A growth factor-induced, spatially organizing cytoskeletal module enables rapid and persistent fibroblast migration.
Martin Katrin, Vilela Marco, Jeon Noo Li, Danuser Gaudenz, Pertz Olivier (2014), A growth factor-induced, spatially organizing cytoskeletal module enables rapid and persistent fibroblast migration., in Developmental cell, 30(6), 701-16.
A versatile toolkit to produce sensitive FRET biosensors to visualize signaling in time and space.
Fritz Rafael, Letzelter Michel, Reimann Andreas, Martin Katrin, Fusco Ludovico, Ritsma Laila, Ponsionen B, Fluri Erika, Schulte-Merker Stefan, Van Rheenen Jacco, Pertz Olivier (2014), A versatile toolkit to produce sensitive FRET biosensors to visualize signaling in time and space., in Science Signaling, 2(285), 1-7.
Assessment of Rho GTPase signaling during neurite outgrowth
Feltrin D., Pertz O. (2012), Assessment of Rho GTPase signaling during neurite outgrowth, in Francesco Rivero (ed.), Humana Press, England, 181-94.
Growth Cone MKK7 mRNA Targeting Regulates MAP1b-Dependent Microtubule Bundling to Control Neurite Elongation
Feltrin D., Fusco L., Witte H., Moretti F., Martin K., Letzelter M., Fluri E., Scheiffele P., Pertz O. (2012), Growth Cone MKK7 mRNA Targeting Regulates MAP1b-Dependent Microtubule Bundling to Control Neurite Elongation, in PLoS Biol, 10, 1001439-1001439.

Collaboration

Group / person Country
Types of collaboration
Gaudenz Danuser United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Michael Bustin,National Cancer Institute United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Noo Li Jeon Korean Republic (South Korea) (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Society for Neuroscience meeting Poster Dissecting a spatio-temporal Rho GTPase signaling network regulating neuronal growth cone extension 09.11.2013 San Diego, United States of America Azarias Guillaume;
Quantissue FRET course Talk given at a conference FRET imaging 26.09.2013 Barcelona, Spain Pertz Olivier;
The 2013 International COS Symposium Building Beauty: from Genes to shape Talk given at a conference growth factor induced persistent fibroblast migration requires front/back mechanical insulation 21.06.2013 heidelberg, Germany Pertz Olivier;
2nd Swiss Image-Image Based Screening Conference Talk given at a conference A high content imaging platform to study spatio-temporal signaling networks during neuronal differentiation 10.06.2013 Lausanne, Switzerland Pertz Olivier;
From spatial signalling to sensing spatiality Poster Growth cone local mRNA translation of nuclear proteins in the spatio-temporal regulation of neurite outgrowth 24.04.2013 dead sea, Israel Moretti Fancesca;
From spatial signalling to sensing spatiality Talk given at a conference GROWTH FACTOR INDUCED POLARIZED FIBROBLAST MIGRATION REQUIRES A PODOSOME FRONT-BACK MECHANICAL INSULATION MODULE 24.04.2013 dead sea, Israel Pertz Olivier;
RNA 2013. The Eighteenth Annual Meeting of the RNA Society Poster Growth cone local mRNA translation of nuclear proteins in the spatio-temporal regulation of neurite outgrowth 11.04.2013 davos, Switzerland Moretti Fancesca;
UNIL DMF Talk given at a conference Saptio-temporal Rho GTPase signaling programs during neurite outgrowth 15.11.2012 Lausanne, Switzerland Pertz Olivier;
Biochemical society of Argentina annual meeting, Mendoza, Argentina Talk given at a conference Saptio-temporal Rho GTPase signaling programs during neurite outgrowth 29.10.2012 Mendoza, Argentina Pertz Olivier;


Communication with the public

Communication Title Media Place Year
Other activities science slam basel German-speaking Switzerland 2013

Associated projects

Number Title Start Funding scheme
114853 Spatio-temporal Rho GTPase signaling mechanisms during directed cell migration 01.12.2007 SNSF Professorships
149923 Optogenetic control of receptor tyrosine kinase signaling to manipulate cell fate 01.02.2014 Project funding (Div. I-III)

Abstract

The purpose of this grant proposal is to study spatio-temporal Rho GTPase signaling mechanisms to the cytoskeleton during cell migration. An essential emphasis will be to study these signaling events at the spatial and temporal scales at which they are occurring (e.g. single microns and tens of seconds respectively). This will take advantage of the novel tools that were developed in the framework of the previous SNF grant proposal. Using 1. a novel generation of FRET-based sensors that monitor Rho GTPase activation, and 2. microfluidic platforms that allow to induce standardized, robust cell migration behaviors, we propose to study spatio-temporal Rho GTPase signaling programs during two robust prototypical cell migration systems:- haptokinesis (cell migration in response to integrin signaling)- PDGF chemokinesis (cell migration in response to stimulation with the soluble chemokine platelet derived growth factor).Our preliminary data shows that both cell migration systems use different actin and adhesion dynamics, that parallel different cell morphodynamics and lead to different migration speeds. The hypothesis relevant to this proposal is that this correlates with different Rho GTPase signaling programs. An important feature of the rapid PDGF chemokinesis cell migration mode is that it allows a high co-ordination between the leading edge and the retracting tail of the cell allowing for robust assessment how both processes are linked.Specifically, we will:- Study the dynamic behavior of a panel of cytoskeletal and adhesion markers in both cell migration modes.- Study the spatio-temporal patterns of RhoA, Rac1 and Cdc42 activity in both cell migration modes.This will then allow to merge these datasets to produce an integrated view of how spatio-temporal Rho GTPase signaling integrates with the different cytoskeletal and adhesion dynamics characteristic of each cell migration mode. This will also allow to put specific spatio-temporal Rho GTPase signaling events in a correct contextual background.We will then perturbate a set of Rac1 activators (GEFs) that are known to signal downstream of integrins or receptor tyrosine kinases (PDGF chemokinesis) and explore how this affects both cell migration modes. The hypothesis relevant to this aim is that these different GEFs regulate spatio-temporal pools of Rac1 with specific functions in time and space. This should again put each GEF in a specific context and extend previous models in which these GEFs has been studied independently in a large variety of cellular contexts.We foresee that this study will allow to significantly extend previous models of cell migration by providing an integrated view of how Rho GTPases regulate and are regulated by cytoskeletal and adhesion dynamics in two prototypical cell migration systems. This should provide a novel paradigm for spatio-temporal Rho GTPase signaling. A clear understanding of these signaling pathways might by example allow to specifically target a given cell migration mode and could be the starting point to design drugs for clinically relevant cell migration events. An example could be the cell migration events that occur during inflammation that results from PDGF-induced fibroblast recruitment to a wound during wound healing.
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