CYRI-A is recruited to macropinocytic cups and mediates integrin uptake, limiting invasive migration

Le, Hoang Anh (2021) CYRI-A is recruited to macropinocytic cups and mediates integrin uptake, limiting invasive migration. PhD thesis, University of Glasgow.

Abstract

In this thesis, we explore the function of a novel protein called CYRI-A through the use of biochemical, biophysical and microscopical techniques. CYRI-A belongs to the group of protein of unknown function. The previous work from our lab described its cousin protein CYRI-B to be the first negative regulator of the Scar/WAVE complex, hence regulating cell migration. Here, through the use of microscopical analysis, we unexpectedly discover the function of CYRI-A as a novel regulator of macropinocytosis. We found that CYRI-A is transiently recruited to the macropinocytic cups, at which it binds and sequesters active Rac1 and suppressing actin polymerisation. This drives the maturation and completion of the macropinocytic cups. In cancer cells, we also found that CYRI-dependent macropinocytosis is important for integrin internalisation. Thus, cells lacking CYRIs express a higher level of surface integrins, which affects its migration, adhesion, and invasion capacity. In a collaboration with the Ismail's group, we also solved the crystal structure of CYRI-B, and discovered that CYRIs are also able to dimerise with each other. This dimerisation directly competes with active Rac1 binding, adding an additional layer of regulation to CYRI. Overall, this thesis provides a careful analysis of the kinetics and localisation of CYRI-A and its novel function as a regulator of macropinocytosis.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: CYRI, Fam49, macropinocytosis, Rac1, Scar/WAVE, intergins, cancer, migration.
• Subjects: Q Science > QH Natural history > QH301 Biology; R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences > Beatson Institute of Cancer Research
• Supervisor's Name: Machesky, Dr. Laura
• Date of Award: 2021
• Depositing User: Dr HOANG ANH LE
• Unique ID: glathesis:2021-81959
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 29 Jan 2021 09:02
• Last Modified: 03 Feb 2021 15:27
• Thesis DOI: 10.5525/gla.thesis.81959
• URI: https://theses.gla.ac.uk/id/eprint/81959