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FEDER, Grant/Award Number: RTI2018-094093-B-I00; Ministerio de Economia y Competitividad, Grant/Award Number: RTI2018-096724-B-C21; Ministerio de Ciencia, Innovacion y Universidades, Grant/Award Number: RTI2018-094093-B-I00; Agencia Estatal de investigacion, Grant/Award Number: RTI2018-094093-B-I00; Fundacion leticia castillejo, Grant/Award Number: N/A; Generalitat Valenciana, Grant/Award Number: PROMETEO/2016/006

Analysis of institutional authors

Roche, OAuthorSanchez-Perez, IAuthorBelandia, BAuthor

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October 25, 2021
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ERK5 signalling pathway is a novel target of sorafenib: Implication in EGF biology

Publicated to:JOURNAL OF CELLULAR AND MOLECULAR MEDICINE. 25 (22): 10591-10603 - 2021-11-01 25(22), DOI: 10.1111/jcmm.16990

Authors: Ortega-Muelas, Marta; Roche, Olga; Fernandez-Aroca, Diego M; Fernandez-Aroca, Diego M; Encinar, Jose A; Encinar, Jose A; Albandea-Rodriguez, David; Arconada-Luque, Elena; Pascual-Serra, Raquel; Munoz, Ismael; Sanchez-Perez, Isabel; Belandia, Borja; Ruiz-Hidalgo, Maria J; Ruiz-Hidalgo, Maria J; Sanchez-Prieto, Ricardo

Affiliations

UAM, Dept Bioquim, Fac Med,Unidad Asociada Biomed UCLM, Inst Invest Biomed Alberto Sols,CSIC,Unidad Asoci, Madrid, Spain - Author
UAM, Unidad Asociada Biomed UCLM, Unidad Asociada Al CSIC, Dept Biol Canc,Inst Invest Biomed Alberto Sols,CS, Madrid, Spain - Author
Univ Castilla La Mancha UCLM, Inst Invest Biomed Alberto Sols, Consejo Super Invest Cient IIBM, CSIC, Albacete, Spain - Author
Univ Castilla La Mancha, Area Bioquim & Biol Mol, Fac Med, Albacete, Spain - Author
Univ Castilla La Mancha, Fac Med, Dept Ciencias Med, Albacete, Spain - Author
Univ Castilla La Mancha, Lab Oncol Mol, Unidad Med Mol,Unidad Asociada Al CSIC, Ctr Reg Invest Biomed,Unidad Asociada Biomed UCLM, Albacete, Spain - Author
Univ Miguel Hernandez UMH, Inst Biol Mol & Celular IBMC, Elche, Spain - Author
Univ Miguel Hernandez UMH, Inst Invest Desarrollo & Innovac Biotecnol Elche, Elche, Spain - Author
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Abstract

Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumour effect related to biological processes as proliferation, migration or invasion, among others. Initially designed as a Raf inhibitor, Sorafenib was later shown to also block key molecules in tumour progression such as VEGFR and PDGFR. In addition, sorafenib has been connected with key signalling pathways in cancer such as EGFR/EGF. However, no definitive clue about the molecular mechanism linking sorafenib and EGF signalling pathway has been established so far. Our data in HeLa, U2OS, A549 and HEK293T cells, based on in silico, chemical and genetic approaches demonstrate that the MEK5/ERK5 signalling pathway is a novel target of sorafenib. In addition, our data show how sorafenib is able to block MEK5-dependent phosphorylation of ERK5 in the Ser218/Tyr220, affecting the transcriptional activation associated with ERK5. Moreover, we demonstrate that some of the effects of this kinase inhibitor onto EGF biological responses, such as progression through cell cycle or migration, are mediated through the effect exerted onto ERK5 signalling pathway. Therefore, our observations describe a novel target of sorafenib, the ERK5 signalling pathway, and establish new mechanistic insights for the antitumour effect of this multikinase inhibitor.

Keywords

egferk5mek5ActivationCombinationEgfEpidermal-growth-factorErk5Hepatocellular-carcinoma cellsInhibitionMek5Multicenter phase-iiProliferationProtein-kinaseRaf/mek/erk pathwayResistanceSorafenib

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal JOURNAL OF CELLULAR AND MOLECULAR MEDICINE due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2021, it was in position 54/139, thus managing to position itself as a Q2 (Segundo Cuartil), in the category Medicine, Research & Experimental. Notably, the journal is positioned en el Cuartil Q2 para la agencia Scopus (SJR) en la categoría Molecular Medicine.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 1.36, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-08, the following number of citations:

  • WoS: 5
  • Scopus: 7
  • Europe PMC: 4

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-08:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 5.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 5 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 1.
  • The number of mentions on the social network X (formerly Twitter): 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.