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The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein–protein interaction in glioblastoma

BACKGROUND: Targeted approaches for inhibiting epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs) in glioblastoma (GBM) have led to therapeutic resistance and little clinical benefit, raising the need for the development of alternative strategies. Endogenous LRIG1 (Le...

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Autores principales: Neirinckx, Virginie, Hau, Ann-Christin, Schuster, Anne, Fritah, Sabrina, Tiemann, Katja, Klein, Eliane, Nazarov, Petr V, Matagne, André, Szpakowska, Martyna, Meyrath, Max, Chevigné, Andy, Schmidt, Mirko H H, Niclou, Simone P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212925/
https://www.ncbi.nlm.nih.gov/pubmed/32642659
http://dx.doi.org/10.1093/noajnl/vdz024
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author Neirinckx, Virginie
Hau, Ann-Christin
Schuster, Anne
Fritah, Sabrina
Tiemann, Katja
Klein, Eliane
Nazarov, Petr V
Matagne, André
Szpakowska, Martyna
Meyrath, Max
Chevigné, Andy
Schmidt, Mirko H H
Niclou, Simone P
author_facet Neirinckx, Virginie
Hau, Ann-Christin
Schuster, Anne
Fritah, Sabrina
Tiemann, Katja
Klein, Eliane
Nazarov, Petr V
Matagne, André
Szpakowska, Martyna
Meyrath, Max
Chevigné, Andy
Schmidt, Mirko H H
Niclou, Simone P
author_sort Neirinckx, Virginie
collection PubMed
description BACKGROUND: Targeted approaches for inhibiting epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs) in glioblastoma (GBM) have led to therapeutic resistance and little clinical benefit, raising the need for the development of alternative strategies. Endogenous LRIG1 (Leucine-rich Repeats and ImmunoGlobulin-like domains protein 1) is an RTK inhibitory protein required for stem cell maintenance, and we previously demonstrated the soluble ectodomain of LRIG1 (sLRIG1) to potently inhibit GBM growth in vitro and in vivo. METHODS: Here, we generated a recombinant protein of the ectodomain of LRIG1 (sLRIG1) and determined its activity in various cellular GBM models including patient-derived stem-like cells and patient organoids. We used proliferation, adhesion, and invasion assays, and performed gene and protein expression studies. Proximity ligation assay and NanoBiT complementation technology were applied to assess protein–protein interactions. RESULTS: We show that recombinant sLRIG1 downregulates EGFRvIII but not EGFR, and reduces proliferation in GBM cells, irrespective of their EGFR expression status. We find that sLRIG1 targets and downregulates a wide range of RTKs, including AXL, and alters GBM cell adhesion. Mechanistically, we demonstrate that LRIG1 interferes with AXL but not with EGFR dimerization. CONCLUSIONS: These results identify AXL as a novel sLRIG1 target and show that LRIG1-mediated RTK downregulation depends on direct protein interaction. The pan-RTK inhibitory activity of sLRIG1 warrants further investigation for new GBM treatment approaches.
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spelling pubmed-72129252020-07-07 The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein–protein interaction in glioblastoma Neirinckx, Virginie Hau, Ann-Christin Schuster, Anne Fritah, Sabrina Tiemann, Katja Klein, Eliane Nazarov, Petr V Matagne, André Szpakowska, Martyna Meyrath, Max Chevigné, Andy Schmidt, Mirko H H Niclou, Simone P Neurooncol Adv Basic and Translational Investigations BACKGROUND: Targeted approaches for inhibiting epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs) in glioblastoma (GBM) have led to therapeutic resistance and little clinical benefit, raising the need for the development of alternative strategies. Endogenous LRIG1 (Leucine-rich Repeats and ImmunoGlobulin-like domains protein 1) is an RTK inhibitory protein required for stem cell maintenance, and we previously demonstrated the soluble ectodomain of LRIG1 (sLRIG1) to potently inhibit GBM growth in vitro and in vivo. METHODS: Here, we generated a recombinant protein of the ectodomain of LRIG1 (sLRIG1) and determined its activity in various cellular GBM models including patient-derived stem-like cells and patient organoids. We used proliferation, adhesion, and invasion assays, and performed gene and protein expression studies. Proximity ligation assay and NanoBiT complementation technology were applied to assess protein–protein interactions. RESULTS: We show that recombinant sLRIG1 downregulates EGFRvIII but not EGFR, and reduces proliferation in GBM cells, irrespective of their EGFR expression status. We find that sLRIG1 targets and downregulates a wide range of RTKs, including AXL, and alters GBM cell adhesion. Mechanistically, we demonstrate that LRIG1 interferes with AXL but not with EGFR dimerization. CONCLUSIONS: These results identify AXL as a novel sLRIG1 target and show that LRIG1-mediated RTK downregulation depends on direct protein interaction. The pan-RTK inhibitory activity of sLRIG1 warrants further investigation for new GBM treatment approaches. Oxford University Press 2019-09-06 /pmc/articles/PMC7212925/ /pubmed/32642659 http://dx.doi.org/10.1093/noajnl/vdz024 Text en © The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Basic and Translational Investigations
Neirinckx, Virginie
Hau, Ann-Christin
Schuster, Anne
Fritah, Sabrina
Tiemann, Katja
Klein, Eliane
Nazarov, Petr V
Matagne, André
Szpakowska, Martyna
Meyrath, Max
Chevigné, Andy
Schmidt, Mirko H H
Niclou, Simone P
The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein–protein interaction in glioblastoma
title The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein–protein interaction in glioblastoma
title_full The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein–protein interaction in glioblastoma
title_fullStr The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein–protein interaction in glioblastoma
title_full_unstemmed The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein–protein interaction in glioblastoma
title_short The soluble form of pan-RTK inhibitor and tumor suppressor LRIG1 mediates downregulation of AXL through direct protein–protein interaction in glioblastoma
title_sort soluble form of pan-rtk inhibitor and tumor suppressor lrig1 mediates downregulation of axl through direct protein–protein interaction in glioblastoma
topic Basic and Translational Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212925/
https://www.ncbi.nlm.nih.gov/pubmed/32642659
http://dx.doi.org/10.1093/noajnl/vdz024
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