G5 Doctoral dissertation (article)

Functional and molecular characterization of potential oncogene Sharpin




List of Authors: Khan Meraj Hasan

Publisher: University of Turku

Place: Turku

Publication year: 2018

ISBN: 978-951-29-7333-0

eISBN: 978-951-29-7334-7

URL: http://urn.fi/URN:ISBN:978-951-29-7334-7


Abstract

Sharpin (SHANK‐Associated RH Domain Interactor) is a multifunctional adaptor protein that interacts with other proteins and regulates their functions. For example, Sharpin is a subunit of the linear ubiquitination assembly complex (LUBAC), which promotes NF‐κB activity. Sharpin also acts as a negative regulator of PTEN, integrins, T cell receptor and Caspase 1.

In this thesis, I report the first interactome of Sharpin. The interactome identified many novel Sharpin interactors and suggested several new pathways regulated by Sharpin. In addition, I confirmed the direct interaction of Sharpin with the Arp2/3 complex, several members of which were in the Sharpin interactome. Importantly, this interaction is physiologically relevant as Arp2/3‐dependent lamellipodia formation and cell migration are significantly affected if this interaction is hampered. Previously, Sharpin had been reported to be essential for the last step of granulocyte transmigration; the release of the trailing edge after crossing the endothelium. The role of Sharpin in the early steps of granulocyte transmigration has remained unknown. However, in this thesis, using intravital real‐time imaging experiments on postcapillary veins in the cremaster muscles of wild‐type (wt) and Sharpin‐deficient mice (Sharpindeficient mice, hereafter also called Sharpincpdm or Sharpin lacking mice), I showed that Sharpin deficient granulocytes are unable to switch from fast rolling to slow rolling and to firmly adhere, thus showing that Sharpin regulates the early steps of transmigration as well.


Last updated on 2021-24-06 at 08:12