Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial–Mesenchymal Transition in Cancer

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Abstract

Epithelial–mesenchymal transition (EMT) is a reversible cellular process, characterized by changes in gene expression and activation of proteins, favoring the trans-differentiation of the epithelial phenotype to a mesenchymal phenotype. This process increases cell migration and invasion of tumor cells, progression of the cell cycle, and resistance to apoptosis and chemotherapy, all of which support tumor progression. One of the signaling pathways involved in tumor progression is the MAPK pathway. Within this family, the ERK subfamily of proteins is known for its contributions to EMT. The ERK subfamily is divided into typical (ERK 1/2/5), and atypical (ERK 3/4/7/8) members. These kinases are overexpressed and hyperactive in various types of cancer. They regulate diverse cellular processes such as proliferation, migration, metastasis, resistance to chemotherapy, and EMT. In this context, in vitro and in vivo assays, as well as studies in human patients, have shown that ERK favors the expression, function, and subcellular relocalization of various proteins that regulate EMT, thus promoting tumor progression. In this review, we discuss the mechanistic roles of the ERK subfamily members in EMT and tumor progression in diverse biological systems.

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RAS oncogenes: the first 30 years.

Marcos Malumbres, Mariano Barbacid (2003)

From the pioneering work with acute transforming retroviruses to the current post-genomic era, RAS genes have always been at the leading edge of signal transduction and molecular oncology. Yet, a complete understanding of RAS function and dysfunction - mainly in human cancer - is still to come. The knowledge that has accumulated since their discovery 30 years ago has, however, been remarkable, and should pave the way for not only solving the outstanding issues regarding RAS biology, but also for developing efficacious drugs that could have a significant impact on cancer treatment.

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The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions.

Seunghee Yoon, Rony Seger (2006)

The extracellular signal-regulated kinase (ERK) cascade is a central pathway that transmits signals from many extracellular agents to regulate cellular processes such as proliferation, differentiation and cell cycle progression. The signaling via the ERK cascade is mediated by sequential phosphorylation and activation of protein kinases in the different tiers of the cascade. Although the main core phosphorylation chain of the cascade includes Raf kinases, MEK1/2, ERK1/2 (ERKs) and RSKs, other alternatively spliced forms and distinct components exist in the different tiers, and participate in ERK signaling under specific conditions. These components enhance the complexity of the ERK cascade and thereby, enable the wide variety of functions that are regulated by it. Another factor that is important for the dissemination of ERKs' signals is the multiplicity of the cascade's substrates, which include transcription factors, protein kinases and phosphatases, cytoskeletal elements, regulators of apoptosis, and a variety of other signaling-related molecules. About 160 substrates have already been discovered for ERKs, and the list of these substrates, as well as the function and mechanism of activation of representative substrates, are described in the current review. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Understanding of these processes may provide a full picture of the distinct, and even opposing cellular processes that are regulated by the ERK cascade.

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Coordinating ERK/MAPK signalling through scaffolds and inhibitors.

Walter Kolch (2005)

The pathway from Ras through Raf and MEK (MAPK and ERK kinase) to ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) regulates many fundamental cellular processes. Recently, a number of scaffolding proteins and endogenous inhibitors have been identified, and their important roles in regulating signalling through this pathway are now emerging. Some scaffolds augment the signal flux, but also mediate crosstalk with other pathways; certain adaptors target MEK-ERK/MAPK complexes to subcellular localizations; others provide regulated inhibition. Computational modelling indicates that, together, these modulators can determine the dynamic biological behaviour of the pathway.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 13 June 2019

Publication date Collection: June 2019

Volume: 20

Issue: 12

Electronic Location Identifier: 2885

Affiliations

[1 ]Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas s/n Chilpancingo, Gro. 39090, Mexico; monse-olea@ 123456live.com.mx (M.O.-F.); miriamzuniga@ 123456uagro.mx (M.D.Z.-E.); ecastaneda@ 123456uagro.mx (E.C.-S.)

[2 ]Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas s/n Chilpancingo, Gro. 39090, Mexico; mamendoza@ 123456uagro.mx (M.A.M.-C.); hugordzrz@ 123456outlook.com (H.A.R.-R.); carlos2pineda@ 123456hotmail.com (C.O.-P.)

[3 ]Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA

Author notes

[* ]Correspondence: Teresita.Padilla@ 123456umassmed.edu or terepadillabenavides@ 123456gmail.com (T.P.-B.); nnavarro@ 123456uagro.mx (N.N.-T.); Tel.: +(1)-508-856-5204 (T.P.-B.); +(52)-747-472-5503 (N.N.-T.)

Author information

Monserrat Olea-Flores https://orcid.org/0000-0003-1813-9062

Miriam Daniela Zuñiga-Eulogio https://orcid.org/0000-0003-2904-8350

Miguel Angel Mendoza-Catalán https://orcid.org/0000-0002-6247-8590

Teresita Padilla-Benavides https://orcid.org/0000-0002-4624-0822

Napoleón Navarro-Tito https://orcid.org/0000-0003-4911-0545

Article

Publisher ID: ijms-20-02885

DOI: 10.3390/ijms20122885

PMC ID: 6627365

PubMed ID: 31200510

SO-VID: e9605b5b-8b2c-40eb-9aae-e05f1aec28aa

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial–Mesenchymal Transition in Cancer

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Neuronal Signaling

Most cited references 186

RAS oncogenes: the first 30 years.

The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions.

Coordinating ERK/MAPK signalling through scaffolds and inhibitors.

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