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    Post-translational control of b-arrestin 2 cytonuclear shuttling


    Elodie Tepaz


    May 14th 1:30 pm 2019

    Rosalind Franklin room, 2nd floor
    Institut Cochin, 22 rue Méchain, Paris 75014

    Supervisor: Mark SCOTT

    Summary: β-arrestins (β-arrs) are multifunctional scaffold proteins that provide a link between external cell inputs and functional cellular outputs. They play a central role in the regulation of signal transduction cascades by acting as "hubs" to orchestrate the activity and/or the subcellular localization of their protein partners, which ultimately gives rise to an appropriate cell response. There are two β-arr isoforms, namely β-arr1 and β-arr2, which share high sequence homology and structural conservation. While the b-arrs often display conserved overlapping roles, decisive differences between the isoforms also exist. A striking example of this is the subcellular distribution of the β-arr isoforms. While b-arr1 is distributed both in cytoplasmic and nuclear compartments, b-arr2 is constitutively exported from the nucleus due to a nuclear export signal in its C-terminus that is absent in β-arr1. β-arr2 therefore undergoes constitutive nucleocytoplasmic shuttling enabling the displacement of nuclear binding cargoes, such as Mdm2 the major negative regulator of tumour suppressor p53. This effect on Mdm2 results in increased p53-mediated transcription and a cell cycle block. While the nuclear export mechanism of β -arr2 has been well characterized the molecular mechanisms that control β-arr2 nuclear import and that define the cytonuclear architecture of β-arr2 distribution remain unexplored.

    The body of work presented in this thesis focuses on the molecular mechanisms that control β-arr2 nuclear import and how this impacts the Mdm2/p53 loop. The data uncover a previously unappreciated mechanism of β-arr2 nuclear import, which has consequences for β-arr2 nuclear transit and cellular Mdm2 distribution.


    Keywords:  β -arrestins, nucleocytoplasmic shuttling, Mdm2, Cancer