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Regulation of the actin cytoskeleton in health and disease


Department of Biochemistry

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Dr J Gallop No more applications being accepted Awaiting Funding Decision/Possible External Funding

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, including HIV and SARS-CoV2, 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. One current area of interest is how membrane signalling lipids are involved in the regulation of filopodia formation. Phosphoinositide 3-kinases (PI3Ks) are targeted therapeutically and while it is clear that the PI3K/PTEN pathway regulates the actin cytoskeleton, our molecular and cellular understanding of this process remains rudimentary. We are working with the SNX9/18/33 family of actin regulators that are implicated in neuronal function and cancer metastasis and are downstream of PI3K.

Our aims include (1) identifying the molecular basis of SNX9 function in filopodia using a panel of antibodies that we have created in collaboration with AstraZeneca (2) measuring the dynamics actin regulators alongside acute perturbation of phosphoinositide signalling during filopodial initiation, extension and retraction in neuronal growth cones (3) investigating filopodia mechanisms in cancer cell lines.

References

1. 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.

2. 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.

3. Dobramysl U*, Jarsch IK*, Shimo H*, Inoue Y*, Richier B, Mason J, Gadsby JR, Walrant A, Butler R, Hannezo E, Simons BD, Gallop JL. Constrained actin dynamics emerges from variable compositions of actin regulatory protein complexes. 2019 bioRxiv 525725.

4. Richier B*, Inoue Y*, Dobramysl U, Friedlander J, Brown NH, Gallop JL. Integrin signaling downregulates filopodia in muscle-tendon attachment. J Cell Sci. 2018 131(16).5.

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. Urbančič 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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