Orchestration of adhesion signalling networks by the tensins and their impact in cell motility and matrix remodelling.
Lead Research Organisation:
University of Manchester
Department Name: School of Biological Sciences
Abstract
Tissues in our body consist of a meshwork of fibrillar material and living cells. The cells continuously sense and produce this fibrillar material, the so-called extracellular matrix (ECM), which surrounds the cells and to which they can attach to. Cell-ECM communication is particularly important during regeneration processes that require specific cellular responses to changing ECM environments. Cellular responses include changes in motile behaviour (e.g. closing of wounds) and also active reorganisation of their ECM when forming new functional tissue. Many studies have focused on how cells detect (sense) environmental signals, but we are still far from understanding how these are translated into signals that promote specific cellular responses.
The extracellular environment of cells alters enormously particularly during ageing, injury and certain diseases. For example, the mechanical properties of the ECM influences tumour progression, and stiffening of ECM causes fibrosis (excess of matrix production), which in turn can lead to malfunctioning of the affected tissues. Intriguingly, cells produce and simultaneously respond to these environmental changes. Understanding this process is critically important if we want to get a step closer to treating the roots of diseases and promote regeneration.
Cells sense their environment by grabbing and pulling the neighbouring extracellular fibrillar material using surface proteins called integrins. These integrins not only bind to the environment of the cells but also connect to a skeleton inside the cells (cytoskeleton). This link is not direct but is regulated by components that couple the two. We published a number of manuscripts showing that two of these coupling proteins, called talin and vinculin, are central to sensing environmental changes. They are particularly important for measuring the stiffness of their surroundings and they control cell migration. In this proposal we present important pilot data demonstrating that members of the tensin protein family, which are critical for ECM reorganisation, interact with a variety of adhesion regulatory proteins including talin and vinculin. How these interactions are mediated, and how different tensin family members are linked to the wider network of proteins that couple integrins to the cytoskeleton, is unclear. Additionally, how these different interactions influence cell behaviour and matrix remodelling is unknown. We will address this problem using long-standing expertise in the fields of integrin mediated cell-matrix interactions in combination with the powerful novel methods established in the Ballestrem laboratory.
The proposed research aims are: (i) to identify key interaction partners of tensin; (ii) to determine how interactions between tensin and its binding partners are regulated and how they contribute to tensin recruitment to cell-matrix adhesion sites; (iii) to investigate how tensins, together with their interaction partners, contribute ECM remodelling and cell motility.
To reach our goals, we will an interdisciplinary approach of cutting edge microscopy, biochemisty and molecular biology techniques with the aim to gain a better understanding of mechanisms that are fundamental for the generation of functional tissues. Ultimately, the knowledge gained may lead to the development of new way to prevent diseases (e.g. cancer, fibrosis) and promote regeneration (wound healing).
The extracellular environment of cells alters enormously particularly during ageing, injury and certain diseases. For example, the mechanical properties of the ECM influences tumour progression, and stiffening of ECM causes fibrosis (excess of matrix production), which in turn can lead to malfunctioning of the affected tissues. Intriguingly, cells produce and simultaneously respond to these environmental changes. Understanding this process is critically important if we want to get a step closer to treating the roots of diseases and promote regeneration.
Cells sense their environment by grabbing and pulling the neighbouring extracellular fibrillar material using surface proteins called integrins. These integrins not only bind to the environment of the cells but also connect to a skeleton inside the cells (cytoskeleton). This link is not direct but is regulated by components that couple the two. We published a number of manuscripts showing that two of these coupling proteins, called talin and vinculin, are central to sensing environmental changes. They are particularly important for measuring the stiffness of their surroundings and they control cell migration. In this proposal we present important pilot data demonstrating that members of the tensin protein family, which are critical for ECM reorganisation, interact with a variety of adhesion regulatory proteins including talin and vinculin. How these interactions are mediated, and how different tensin family members are linked to the wider network of proteins that couple integrins to the cytoskeleton, is unclear. Additionally, how these different interactions influence cell behaviour and matrix remodelling is unknown. We will address this problem using long-standing expertise in the fields of integrin mediated cell-matrix interactions in combination with the powerful novel methods established in the Ballestrem laboratory.
The proposed research aims are: (i) to identify key interaction partners of tensin; (ii) to determine how interactions between tensin and its binding partners are regulated and how they contribute to tensin recruitment to cell-matrix adhesion sites; (iii) to investigate how tensins, together with their interaction partners, contribute ECM remodelling and cell motility.
To reach our goals, we will an interdisciplinary approach of cutting edge microscopy, biochemisty and molecular biology techniques with the aim to gain a better understanding of mechanisms that are fundamental for the generation of functional tissues. Ultimately, the knowledge gained may lead to the development of new way to prevent diseases (e.g. cancer, fibrosis) and promote regeneration (wound healing).
Technical Summary
Cells interact with the extracellular matrix (ECM) through transmembrane adhesion receptors (integrins) that are linked to signalling proteins that regulate cell migration and ECM remodelling/synthesis. Published data suggest that a family of proteins, the tensins, are embedded in a large network of proteins that influence how cells interpret and remodel their ECM. Which proteins tensins interact with and how they transduce signals to and from the ECM is unclear. As these signals affect cell motility and ECM remodelling, our overarching aim is to understand the role of tensin family members in controlling these processes.
Using cutting edge mass spectrometry and a novel mitochondrial targeting system (MTS) that allows visualisation of protein complexes assembled under defined conditions, we will first identify the proteins the tensins associate with. Using MTS, we will then define tensin interaction sites with binding partners and then examine how they contribute to tensin recruitment to cell-matrix adhesions. Pilot data show an interaction between tensin and the mechanosensors talin and vinculin. Based on these data we hypothesise a key role for these associations in the force-dependent maturation of cell-matrix adhesion sites that regulate ECM remodelling and cell movements. We will use advanced fluorescence imaging to investigate how specific interactions contribute to matrix remodelling and cell motility.
Insights from these studies may ultimately lead to the development of new strategies to prevent diverse diseases and promote tissue regeneration.
Using cutting edge mass spectrometry and a novel mitochondrial targeting system (MTS) that allows visualisation of protein complexes assembled under defined conditions, we will first identify the proteins the tensins associate with. Using MTS, we will then define tensin interaction sites with binding partners and then examine how they contribute to tensin recruitment to cell-matrix adhesions. Pilot data show an interaction between tensin and the mechanosensors talin and vinculin. Based on these data we hypothesise a key role for these associations in the force-dependent maturation of cell-matrix adhesion sites that regulate ECM remodelling and cell movements. We will use advanced fluorescence imaging to investigate how specific interactions contribute to matrix remodelling and cell motility.
Insights from these studies may ultimately lead to the development of new strategies to prevent diverse diseases and promote tissue regeneration.
Publications
Atherton P
(2022)
Tensin3 interaction with talin drives the formation of fibronectin-associated fibrillar adhesions.
in The Journal of cell biology
Mana G
(2023)
The ßI domain promotes active ß1 integrin clustering into mature adhesion sites.
in Life science alliance
Description | We have identified a network of proteins that are connected to the adapter protein tensin. We hypothesise that some of these proteins are important for the formation and regeneration of tissues. |
Exploitation Route | Some of the knowledge will be taken further to apply for grant funding to solve the way proteins interact and are involved in tissue organisation. The long-term aim is that this understanding will contribute to the design of drugs/small molecules that can interfere with unwanted excessive production of extracellular matrix which can lead to diseases like fibrosis. |
Sectors | Education Healthcare Manufacturing including Industrial Biotechology |
URL | http://www.ballestremlab.com |
Description | BBSRC pool panel member - Invitation for panel C 2024 |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Invitation on a grant panel for the Executive Agency for Higher Education, Research, Development and Innovation Funding (UEFISCDI) in Rumania. |
Geographic Reach | Europe |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Invitation to the 2023 "pool of experts" for BBSRC applications. |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Laser Surface engineering for osseointegration |
Amount | £49,998 (GBP) |
Organisation | University of Manchester |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2022 |
End | 01/2023 |
Description | Collaboration with Serini laboratory in Turin, Italy |
Organisation | Candiolo Cancer Institute |
Country | Italy |
Sector | Charity/Non Profit |
PI Contribution | Reagents, supervision, contribution to funding acquisition, investigation, visualization, and writing-original draft, review, and editing. |
Collaborator Contribution | Exchange of knowledge |
Impact | DOI 10.26508/lsa.202201388 |
Start Year | 2022 |
Description | Collaboration with Thomas Zacharchenko, Manchester |
Organisation | University of Manchester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Planning and performing all cellular experiments; providing reagents; writing manuscript. |
Collaborator Contribution | Performing all structural experiments; writing the manuscript and exchanging knowledge. |
Impact | doi.org/10.1101/2023.02.23.529676 |
Start Year | 2022 |
Description | European Cytoskeletal Forum (international conference) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | invited talk to experts international experts in the field which sparked questions and discussions. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.europeancytoskeletalforum.org/scientific-programm-ecf-2022 |
Description | GRC international conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Invited talk at GRC conference (Fibronectin, Integrins and Related Molecules Gordon Research Conference); an outstanding conference with international experts in the field. |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.grc.org/fibronectin-integrins-and-related-molecules-conference/2023/ |
Description | GRC international conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Invited talk to an international conference (Grodon Research conference, Signaling by Adhesion Receptors) with academic experts in the field. GRC conferences are the most prestigious conferences in the field. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.grc.org/signaling-by-adhesion-receptors-conference/2022/ |
Description | Hosting of 2 A Level students from Loretto High School in Manchester |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Hosting 2 A level students for one day. Day organisation: Tour through the research lab and imaging facility; introduction in the projects running in the laboratory; presentation of the lab projects with discussions involving laboratory members; outlook discussion for science in gerneral. |
Year(s) Of Engagement Activity | 2024 |
Description | Pint of Science |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Public engagement event "Pint of Science" series in Manchester (UK); joint event with an artist (Sally Gilford); Title: Becoming the Matrix. |
Year(s) Of Engagement Activity | 2022 |
URL | https://pintofscience.co.uk/event/becoming-the-matrix |