Armus dual roles in autophagy and E-cadherin degradation : distinct partners, regulation and implications for cancer patients
Cancer is one of the leading causes of mortality worldwide. Invasion, metastasis and apoptotic evasion are cancer hallmarks. Tumour cell metastasis requires loss of E-cadherin cell-cell adhesion receptor. Apoptotic evasion can be mediated by up-regulation of autophagy, which maintains cellular energ...
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ndltd-bl.uk-oai-ethos.bl.uk-7183762018-10-09T03:26:01ZArmus dual roles in autophagy and E-cadherin degradation : distinct partners, regulation and implications for cancer patientsMohd Naim, Noor FaizahBraga, Vania2015Cancer is one of the leading causes of mortality worldwide. Invasion, metastasis and apoptotic evasion are cancer hallmarks. Tumour cell metastasis requires loss of E-cadherin cell-cell adhesion receptor. Apoptotic evasion can be mediated by up-regulation of autophagy, which maintains cellular energy during metabolic stress in cancer cells. Armus is a TBC/RabGAP protein that regulates both E-cadherin degradation and autophagy by controlling lysosome fusion with late vesicular compartments or autophagosomes. Understanding Armus function in these degradative processes during tumourigenesis may lead to combinatorial inhibition of oncogenic pathways and novel therapeutic targets. Here I address: (i) whether Armus participates in E-cadherin deregulation downstream of oncogenes, (ii) potential mechanisms through which Armus can switch between its function at junctions and autophagosomes and (iii) potential strategies to inhibit Armus intracellular localisation. I found that Armus is involved in Src and H-Ras disruption of E-cadherin junctions in keratinocytes. Armus binds to α-catenin at junctions, while at autophagosomes Armus interacts with autophagy marker, LC3. Incubation with Armus peptides containing LC3-interacting motifs partially blocks Armus function in autophagy. Mutation of the specific residues mediating α-catenin association reduces Armus localisation at cell-cell contacts. The close juxtaposition of LC3 and α-catenin binding at PH domain at Armus N-terminus may suggest additional roles. Armus N-terminus and RabGAP domain interact directly, and residue K480 is critical for binding. This intramolecular interaction may form a closed conformation, and Armus activation may require the release of this auto-inhibition. It is tempting to suggest that protein interactions at the PH domain such as LC3 and α-catenin may modulate Armus auto-inhibition. Alternatively, the phosphoinositide repertoire interacting with the PH domain may contribute to Armus intracellular distribution and activation. Further insights into Armus activation may provide greater understanding of its function in distinct cellular events with implications for tumourigenesis.616.99Imperial College Londonhttps://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.718376http://hdl.handle.net/10044/1/47979Electronic Thesis or Dissertation |
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616.99 Mohd Naim, Noor Faizah Armus dual roles in autophagy and E-cadherin degradation : distinct partners, regulation and implications for cancer patients |
description |
Cancer is one of the leading causes of mortality worldwide. Invasion, metastasis and apoptotic evasion are cancer hallmarks. Tumour cell metastasis requires loss of E-cadherin cell-cell adhesion receptor. Apoptotic evasion can be mediated by up-regulation of autophagy, which maintains cellular energy during metabolic stress in cancer cells. Armus is a TBC/RabGAP protein that regulates both E-cadherin degradation and autophagy by controlling lysosome fusion with late vesicular compartments or autophagosomes. Understanding Armus function in these degradative processes during tumourigenesis may lead to combinatorial inhibition of oncogenic pathways and novel therapeutic targets. Here I address: (i) whether Armus participates in E-cadherin deregulation downstream of oncogenes, (ii) potential mechanisms through which Armus can switch between its function at junctions and autophagosomes and (iii) potential strategies to inhibit Armus intracellular localisation. I found that Armus is involved in Src and H-Ras disruption of E-cadherin junctions in keratinocytes. Armus binds to α-catenin at junctions, while at autophagosomes Armus interacts with autophagy marker, LC3. Incubation with Armus peptides containing LC3-interacting motifs partially blocks Armus function in autophagy. Mutation of the specific residues mediating α-catenin association reduces Armus localisation at cell-cell contacts. The close juxtaposition of LC3 and α-catenin binding at PH domain at Armus N-terminus may suggest additional roles. Armus N-terminus and RabGAP domain interact directly, and residue K480 is critical for binding. This intramolecular interaction may form a closed conformation, and Armus activation may require the release of this auto-inhibition. It is tempting to suggest that protein interactions at the PH domain such as LC3 and α-catenin may modulate Armus auto-inhibition. Alternatively, the phosphoinositide repertoire interacting with the PH domain may contribute to Armus intracellular distribution and activation. Further insights into Armus activation may provide greater understanding of its function in distinct cellular events with implications for tumourigenesis. |
author2 |
Braga, Vania |
author_facet |
Braga, Vania Mohd Naim, Noor Faizah |
author |
Mohd Naim, Noor Faizah |
author_sort |
Mohd Naim, Noor Faizah |
title |
Armus dual roles in autophagy and E-cadherin degradation : distinct partners, regulation and implications for cancer patients |
title_short |
Armus dual roles in autophagy and E-cadherin degradation : distinct partners, regulation and implications for cancer patients |
title_full |
Armus dual roles in autophagy and E-cadherin degradation : distinct partners, regulation and implications for cancer patients |
title_fullStr |
Armus dual roles in autophagy and E-cadherin degradation : distinct partners, regulation and implications for cancer patients |
title_full_unstemmed |
Armus dual roles in autophagy and E-cadherin degradation : distinct partners, regulation and implications for cancer patients |
title_sort |
armus dual roles in autophagy and e-cadherin degradation : distinct partners, regulation and implications for cancer patients |
publisher |
Imperial College London |
publishDate |
2015 |
url |
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.718376 |
work_keys_str_mv |
AT mohdnaimnoorfaizah armusdualrolesinautophagyandecadherindegradationdistinctpartnersregulationandimplicationsforcancerpatients |
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1718772294936952832 |