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Regulation of the actin cytoskeleton in health and disease


   Department of Biochemistry

   Applications accepted all year round  Awaiting Funding Decision/Possible External Funding

Cambridge United Kingdom Biochemistry Biophysics Cancer Biology Cell Biology Developmental Biology Molecular Biology Neuroscience Structural Biology

About the Project

An understanding of the actin cytoskeleton is critical for determining how cells connect to each other, move and have a distinct architecture. Defects in the actin cytoskeleton are associated with disease including genetic diseases of the immune system and kidney absorption, intellectual disabilities and cancer metastasis. Typically for such a fundamental process, the actin machinery is also subverted by pathogens to increase infectivity.

We have a particular interest in long, finger-like protrusions from cells called filopodia. We are asking questions such as: how does the cell make a filopodium in particular place? How are filopodia stabilised in one direction or retracted in response to extracellular cues? How is the distance filopodia reach determined and how is their lifetime tuned to give sufficient opportunity for movement and signalling?

We employ a wide range of methods ranging from protein biochemistry to advanced timelapse and superresolution imaging, cell culture and embryology. Our aims include (1) identifying the molecular basis of actin regulation using a panel of antibodies that we have created in collaboration with AstraZeneca (2) measuring and perturbing the dynamics of actin regulators in neuronal growth cones (3) investigating the roles of SNX9 and SNX18 in cancer cell lines.


References

1. Dobramysl U*, Jarsch IK*, Inoue Y*, Shimo H*, Richier B, Gadsby JR, Mason J, Szałapak A, Ioannou PS, Correia GP, Walrant A, Butler R, Hannezo E, Simons BD, Gallop JL. Stochastic combinations of actin regulatory proteins are sufficient to drive filopodia formation. J Cell Biol. 2021 Apr 5;220(4):e202003052.
2. Berquez M*, Gadsby JR*, Festa BP*, Butler R, Jackson SP, Berno V, Luciani A, Devuyst O†, Gallop JL. The phosphoinositide 3-kinase inhibitor alpelisib restores actin organization and improves proximal tubule dysfunction in vitro and in a mouse model of Lowe syndrome and Dent disease. Kidney Int 2020 98:883-896.
3. Jarsch IK*, Gadsby JR*, A Nuccitelli, J Mason, H Shimo, L Pilloux, B Marzook, CM Mulvey, U Dobramysl, KS Lilley, RD Hayward, TJ Vaughan, CL Dobson, JL Gallop. A direct role for SNX9 in the biogenesis of filopodia. J Cell Biol. 2020 Apr 6;219(4):e201909178.
4. Richier B*, Inoue Y*, Dobramysl U, Friedlander J, Brown NH, Gallop JL. Integrin signaling downregulates filopodia during muscle-tendon attachment.J Cell Sci. 2018 Aug 16;131(16):jcs217133.
5. Daste F*, Walrant A*, Holst MR*, Gadsby JR*, Mason J, Lee JE, Brook D, Mettlen M, Larsson E, Lee SF, Lundmark R, Gallop JL. Control of actin polymerization via the coincidence of phosphoinositides and membrane curvature. J Cell Biol 2017 216:3745-3765.
6. Urbanicic; V, Butler R, Richier B, Peter M, Mason J, Livesey FJ, Holt CE, Gallop JL. Filopodyan: an open-source pipeline for the analysis of filopodia. J Cell Biol 2017 216: 3405-3422.
* equal contribution by authors

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