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Molecular regulation of cell adaptation to tissue stiffness through talin-DLC1 connection in adhesions


Project Description

Cells have an amazing ability to form complex tissues, differentiate and migrate. All these processes are controlled by a network of proteins that constantly change their activity and interactions in response to the environment and intracellular signals in a finely tuned synchrony. In diseases, such as cancer, as well as in ageing, key proteins acquire malignant mutations that cause breakdown in the adaptation mechanism, leading to tumour formation or tissue degradation. The abnormal tissues change composition and mechanical properties, which cause further disruptions and progression of the disease. We identified a set of key proteins, including Rho-GTPase regulator deleted in liver cancer 1 (DLC1) and mechano-transducer talin, that form a critical part of the cell adaptation mechanism. Understanding the regulation of the interaction between these proteins on the molecular level will answer a set of fundamental question of how adapts to the environment. Translation of this knowledge to clinical environment will contribute to the development of new strategies to fight disease and prolong healthy life.

This multi-disciplinary project will combine cutting-edge approaches of structural and cell biology with the advance tissue engineering methods that are established in the laboratories of the three collaborating project supervisors base in Liverpool and Newcastle. The main focus will be on the molecular aspects of cell regulation, while acquiring the complementary expertise in other areas through lab rotation. On completion you will gain expertise in NMR and X-ray crystallography, advanced fluorescent microscopy, and engineering of artificial tissues. This combination of expertise is highly sought-after and will allow you to pursue career in academia or industry.

HOW TO APPLY

Applications should be made by emailing with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to . A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to

Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

(2013). RIAM and Vinculin Binding to Talin Are Mutually Exclusive and Regulate Adhesion Assembly and Turnover. J Biol Chem 288, 8238-8249

(2016). LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex. Structure 24, 1130-1141

(2019) Assessment of corneal substrate biomechanics and its effect on epithelial stem cell maintenance and differentiation. Nature. Comms. doi: 10.1038/s41467-019-09331-6

(2016). SHANK3 structure reveals a Ras-associated domain regulating integrin activation, Nature Cell Biol, 19, 292

(2015). Vinculin controls talin engagement with the actomyosin machinery. Nature Comm. 6, 10038

(2017) Template Curvature Influences Cell Alignment to Create Improved Human Corneal Tissue Equivalents. Advanced Biosystems doi: 10.1002/adbi.201700135

(2019) Membrane tension orchestrates rear retraction in matrix directed cell migration. Developmental Cell https://doi.org/10.1016/j.devcel.2019.09.006

(2019) Local actin nucleation tunes centrosomal microtubule nucleation during passage through mitosis. EMBO J., 3;38(11)

(2018) STEF/TIAM2 mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap. Nature Commun 9, 212

(2017) HRS-WASH axis governs Actin mediated endosomal recycling and cell invasion. J. Cell Biol. 217,2549

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