The EGF Domains of MUC4 Oncomucin Mediate HER2 Binding Affinity and Promote Pancreatic Cancer Cell Tumorigenesis

The HER2 receptor and its MUC4 mucin partner form an oncogenic complex via an extracellular region of MUC4 encompassing three EGF domains that promotes tumor progression of pancreatic cancer (PC) cells. However, the molecular mechanism of interaction remains poorly understood. Herein, we decipher at...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Nicolas Stoup, Maxime Liberelle, Céline Schulz, Sumeyye Cavdarli, Romain Vasseur, Romain Magnez, Fatima Lahdaoui, Nicolas Skrypek, Fabien Peretti, Frédéric Frénois, Xavier Thuru, Patricia Melnyk, Nicolas Renault, Nicolas Jonckheere, Nicolas Lebègue, Isabelle Van Seuningen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	HER2 MUC4 protein–protein interaction pancreatic cancer EGF domain Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/ef25e74cdf49405db2eab06bde6f9620
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ef25e74cdf49405db2eab06bde6f9620
record_format	dspace
spelling	oai:doaj.org-article:ef25e74cdf49405db2eab06bde6f96202021-11-25T17:03:31ZThe EGF Domains of MUC4 Oncomucin Mediate HER2 Binding Affinity and Promote Pancreatic Cancer Cell Tumorigenesis10.3390/cancers132257462072-6694https://doaj.org/article/ef25e74cdf49405db2eab06bde6f96202021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5746https://doaj.org/toc/2072-6694The HER2 receptor and its MUC4 mucin partner form an oncogenic complex via an extracellular region of MUC4 encompassing three EGF domains that promotes tumor progression of pancreatic cancer (PC) cells. However, the molecular mechanism of interaction remains poorly understood. Herein, we decipher at the molecular level the role and impact of the MUC4<sub>EGF</sub> domains in the mediation of the binding affinities with HER2 and the PC cell tumorigenicity. We used an integrative approach combining in vitro bioinformatic, biophysical, biochemical, and biological approaches, as well as an in vivo study on a xenograft model of PC. In this study, we specified the binding mode of MUC4<sub>EGF</sub> domains with HER2 and demonstrate their “growth factor-like” biological activities in PC cells leading to stimulation of several signaling proteins (mTOR pathway, Akt, and β-catenin) contributing to PC progression. Molecular dynamics simulations of the MUC4<sub>EGF</sub>/HER2 complexes led to 3D homology models and identification of binding hotspots mediating binding affinity with HER2 and PC cell proliferation. These results will pave the way to the design of potential MUC4/HER2 inhibitors targeting the EGF domains of MUC4. This strategy will represent a new efficient alternative to treat cancers associated with MUC4/HER2 overexpression and HER2-targeted therapy failure as a new adapted treatment to patients.Nicolas StoupMaxime LiberelleCéline SchulzSumeyye CavdarliRomain VasseurRomain MagnezFatima LahdaouiNicolas SkrypekFabien PerettiFrédéric FrénoisXavier ThuruPatricia MelnykNicolas RenaultNicolas JonckheereNicolas LebègueIsabelle Van SeuningenMDPI AGarticleHER2MUC4protein–protein interactionpancreatic cancerEGF domainNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5746, p 5746 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	HER2 MUC4 protein–protein interaction pancreatic cancer EGF domain Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	HER2 MUC4 protein–protein interaction pancreatic cancer EGF domain Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Nicolas Stoup Maxime Liberelle Céline Schulz Sumeyye Cavdarli Romain Vasseur Romain Magnez Fatima Lahdaoui Nicolas Skrypek Fabien Peretti Frédéric Frénois Xavier Thuru Patricia Melnyk Nicolas Renault Nicolas Jonckheere Nicolas Lebègue Isabelle Van Seuningen The EGF Domains of MUC4 Oncomucin Mediate HER2 Binding Affinity and Promote Pancreatic Cancer Cell Tumorigenesis
description	The HER2 receptor and its MUC4 mucin partner form an oncogenic complex via an extracellular region of MUC4 encompassing three EGF domains that promotes tumor progression of pancreatic cancer (PC) cells. However, the molecular mechanism of interaction remains poorly understood. Herein, we decipher at the molecular level the role and impact of the MUC4<sub>EGF</sub> domains in the mediation of the binding affinities with HER2 and the PC cell tumorigenicity. We used an integrative approach combining in vitro bioinformatic, biophysical, biochemical, and biological approaches, as well as an in vivo study on a xenograft model of PC. In this study, we specified the binding mode of MUC4<sub>EGF</sub> domains with HER2 and demonstrate their “growth factor-like” biological activities in PC cells leading to stimulation of several signaling proteins (mTOR pathway, Akt, and β-catenin) contributing to PC progression. Molecular dynamics simulations of the MUC4<sub>EGF</sub>/HER2 complexes led to 3D homology models and identification of binding hotspots mediating binding affinity with HER2 and PC cell proliferation. These results will pave the way to the design of potential MUC4/HER2 inhibitors targeting the EGF domains of MUC4. This strategy will represent a new efficient alternative to treat cancers associated with MUC4/HER2 overexpression and HER2-targeted therapy failure as a new adapted treatment to patients.
format	article
author	Nicolas Stoup Maxime Liberelle Céline Schulz Sumeyye Cavdarli Romain Vasseur Romain Magnez Fatima Lahdaoui Nicolas Skrypek Fabien Peretti Frédéric Frénois Xavier Thuru Patricia Melnyk Nicolas Renault Nicolas Jonckheere Nicolas Lebègue Isabelle Van Seuningen
author_facet	Nicolas Stoup Maxime Liberelle Céline Schulz Sumeyye Cavdarli Romain Vasseur Romain Magnez Fatima Lahdaoui Nicolas Skrypek Fabien Peretti Frédéric Frénois Xavier Thuru Patricia Melnyk Nicolas Renault Nicolas Jonckheere Nicolas Lebègue Isabelle Van Seuningen
author_sort	Nicolas Stoup
title	The EGF Domains of MUC4 Oncomucin Mediate HER2 Binding Affinity and Promote Pancreatic Cancer Cell Tumorigenesis
title_short	The EGF Domains of MUC4 Oncomucin Mediate HER2 Binding Affinity and Promote Pancreatic Cancer Cell Tumorigenesis
title_full	The EGF Domains of MUC4 Oncomucin Mediate HER2 Binding Affinity and Promote Pancreatic Cancer Cell Tumorigenesis
title_fullStr	The EGF Domains of MUC4 Oncomucin Mediate HER2 Binding Affinity and Promote Pancreatic Cancer Cell Tumorigenesis
title_full_unstemmed	The EGF Domains of MUC4 Oncomucin Mediate HER2 Binding Affinity and Promote Pancreatic Cancer Cell Tumorigenesis
title_sort	egf domains of muc4 oncomucin mediate her2 binding affinity and promote pancreatic cancer cell tumorigenesis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ef25e74cdf49405db2eab06bde6f9620
work_keys_str_mv	AT nicolasstoup theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT maximeliberelle theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT celineschulz theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT sumeyyecavdarli theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT romainvasseur theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT romainmagnez theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT fatimalahdaoui theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT nicolasskrypek theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT fabienperetti theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT fredericfrenois theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT xavierthuru theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT patriciamelnyk theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT nicolasrenault theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT nicolasjonckheere theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT nicolaslebegue theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT isabellevanseuningen theegfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT nicolasstoup egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT maximeliberelle egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT celineschulz egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT sumeyyecavdarli egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT romainvasseur egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT romainmagnez egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT fatimalahdaoui egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT nicolasskrypek egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT fabienperetti egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT fredericfrenois egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT xavierthuru egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT patriciamelnyk egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT nicolasrenault egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT nicolasjonckheere egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT nicolaslebegue egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis AT isabellevanseuningen egfdomainsofmuc4oncomucinmediateher2bindingaffinityandpromotepancreaticcancercelltumorigenesis
_version_	1718412811701321728

The EGF Domains of MUC4 Oncomucin Mediate HER2 Binding Affinity and Promote Pancreatic Cancer Cell Tumorigenesis

Ejemplares similares