Cited by 557Melanoma and MAPK PathwaysProtein Kinase Regulation and GTPase SignalingProtein Tyrosine Phosphatases

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RAF-MEK-ERK pathway in cancer evolution and treatment

Ullah, Rahim, Yin, Qing, Snell, Aidan H., Wan, Lixin·2022·Seminars in Cancer Biology

DOI 10.1016/j.semcancer.2021.05.010

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Abstract

The RAF-MEK-ERK signaling cascade is a well-characterized MAPK pathway involved in cell proliferation and survival. The three-layered MAPK signaling cascade is initiated upon RTK and RAS activation. Three RAF isoforms ARAF, BRAF and CRAF, and their downstream MEK1/2 and ERK1/2 kinases constitute a coherently orchestrated signaling module that directs a range of physiological functions. Genetic alterations in this pathway are among the most prevalent in human cancers, which consist of numerous hot-spot mutations such as BRAF V600E. Oncogenic mutations in this pathway often override otherwise tightly regulated checkpoints to open the door for uncontrolled cell growth and neoplasia. The crosstalk between the RAF-MEK-ERK axis and other signaling pathways further extends the proliferative potential of this pathway in human cancers. In this review, we summarize the molecular architecture and physiological functions of the RAF-MEK-ERK pathway with emphasis on its dysregulations in human cancers, as well as the efforts made to target the RAF-MEK-ERK module using small molecule inhibitors.

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Background

Authors: Ullah, R., Yin, Q., Snell, A. H., & Wan, L.
Affiliations: Moffitt Cancer Center (US)
Corresponding author: Wan, Lixin
ORCID: Yin, Qing
Snell, Aidan H.
Wan, Lixin
Venue: Seminars in Cancer Biology
Publisher: Elsevier BV
Published: 2022-10
Volume: 85
Pages: 123-154
ISSN: 1044-579X (ISSN-L)
DOI: 10.1016/j.semcancer.2021.05.010
OpenAlex: W3160873367
Cited by: 553
References: 506
Citations by year: 2026: 123 · 2025: 164 · 2024: 173 · 2023: 69 · 2022: 19
FWCI: 7.08
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Seminars in Cancer Biology (publishedVersion)
PubMed (publishedVersion)
Funders: Melanoma Research Alliance
Florida Department of Health
American Cancer Society
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords: Raf/MEK/ERK pathway, MAPK signaling, BRAF V600E mutation, Raf isoforms, MEK1/2, ERK1/2, Ras activation, receptor tyrosine kinase signaling, tumor evolution, cancer therapy, small molecule inhibitors, signaling crosstalk, oncogenic mutations
MeSH terms: Humans, Neoplasms, Signal Transduction, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf

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RAF-MEK-ERK pathway in cancer evolution and treatment

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