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

RAF-MEK-ERK pathway in cancer evolution and treatment

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

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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Crossref · 10.1016/j.semcancer.2021.05.010

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  • Activated RAS proteins can interact with many downstream effector proteins, such as RAF kinase, son of sevenless (SOS), phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide dissociation stimulating factors (RalGDS), which regulate cell events such as cell proliferation and apoptosis.

    “Activated RAS proteins can interact with many downstream effector proteins, such as RAF kinase, son of sevenless (SOS), phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide dissociation stimulating factors (RalGDS), which regulate cell events such as cell proliferation and apoptosis.323–325”

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Authors
Ullah, R., Yin, Q., Snell, A. H., & Wan, L.
Affiliations
Moffitt Cancer Center (US)
Corresponding author
Wan, Lixin
Venue
Seminars in Cancer Biology
Publisher
Elsevier BV
Published
2022-10
Volume
85
Pages
123-154
ISSN
1044-579X (ISSN-L)
OpenAlex
W3160873367
Cited by
553
References
506
Citations by year
2026: 123 · 2025: 164 · 2024: 173 · 2023: 69 · 2022: 19 · 2021: 5
FWCI
7.08
Type
journal article
Language
en
Open access
closed
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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