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Eps8 is a convergence point integrating EGFR and integrin trafficking and crosstalk

Nikki R Paul, Joanna R Thomas, Horacio Maldonado, Katarzyna I Wolanska, Ewa J Koper, View ORCID ProfileJonathan D Humphries, View ORCID ProfileAdam Byron, Adams George, Nathan Allen, View ORCID ProfileIan A Prior, View ORCID ProfileCharles H Streuli, View ORCID ProfileMartin J Humphries, View ORCID ProfileMark R Morgan
doi: https://doi.org/10.1101/405043
Nikki R Paul
1Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK
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Joanna R Thomas
2Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK
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Horacio Maldonado
2Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK
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Katarzyna I Wolanska
2Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK
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Ewa J Koper
3Faculty of Biology, Medicine & Health, Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
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Jonathan D Humphries
3Faculty of Biology, Medicine & Health, Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
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Adam Byron
4Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XR, UK
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Adams George
2Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK
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Nathan Allen
2Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK
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Ian A Prior
2Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK
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Charles H Streuli
3Faculty of Biology, Medicine & Health, Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
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Martin J Humphries
3Faculty of Biology, Medicine & Health, Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
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Mark R Morgan
2Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK
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Abstract

Crosstalk between adhesion and growth factor receptors plays a critical role in tissue morphogenesis and repair, and aberrations contribute substantially to neoplastic disease. However, the mechanisms by which adhesion and growth factor receptor signalling are integrated, spatially and temporally, are unclear.

We used adhesion complex enrichment coupled with quantitative proteomic analysis to identify rapid changes to adhesion complex composition and signalling following growth factor stimulation. Bioinformatic network and ontological analyses revealed a substantial decrease in the abundance of adhesion regulatory proteins and co-ordinators of endocytosis within 5 minutes of EGF stimulation. Together these data suggested a mechanism of EGF-induced receptor endocytosis and adhesion complex turnover.

Combinatorial interrogation of the networks allowed a global and dynamic view of adhesion and growth factor receptor crosstalk to be assembled. By interrogating network topology we identified Eps8 as a putative node integrating α5β1 integrin and EGFR functions. Importantly, EGF stimulation promoted internalisation of both α5β1 and EGFR. However, perturbation of Eps8 increased constitutive internalisation of α5β1 and EGFR; suggesting that Eps8 constrains α5β1 and EGFR endocytosis in the absence of EGF stimulation. Consistent with this, Eps8 regulated Rab5 activity and was required for maintenance of adhesion complex organisation and for EGF-dependent adhesion complex disassembly. Thus, by co-ordinating α5β1 and EGFR trafficking mechanisms, Eps8 is able to control adhesion receptor and growth factor receptor bioavailability and cellular contractility.

We propose that during tissue morphogenesis and repair, Eps8 functions to spatially and temporally constrain endocytosis, and engagement, of α5β1 and EGFR in order to precisely co-ordinate adhesion disassembly, cytoskeletal dynamics and cell migration.

Abbreviations
ECM
Extracellular matrix
EGF
Epidermal growth factor
EGFR
Epidermal growth factor receptor
Eps8
Epidermal growth factor receptor pathway substrate 8
GFR
Growth factor receptor
IAC
Integrin-associated complex
MAPK
Mitogen activated protein kinase
MEC
Mammary epithelial cell
MEF
Mouse embryonic fibroblast
PKCα
Protein kinase Cα
TIF
T-antigen immortalised fibroblast
Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 04, 2018.
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Eps8 is a convergence point integrating EGFR and integrin trafficking and crosstalk
Nikki R Paul, Joanna R Thomas, Horacio Maldonado, Katarzyna I Wolanska, Ewa J Koper, Jonathan D Humphries, Adam Byron, Adams George, Nathan Allen, Ian A Prior, Charles H Streuli, Martin J Humphries, Mark R Morgan
bioRxiv 405043; doi: https://doi.org/10.1101/405043
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Eps8 is a convergence point integrating EGFR and integrin trafficking and crosstalk
Nikki R Paul, Joanna R Thomas, Horacio Maldonado, Katarzyna I Wolanska, Ewa J Koper, Jonathan D Humphries, Adam Byron, Adams George, Nathan Allen, Ian A Prior, Charles H Streuli, Martin J Humphries, Mark R Morgan
bioRxiv 405043; doi: https://doi.org/10.1101/405043

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