Cited by 108Melanoma and MAPK PathwaysProtein Kinase Regulation and GTPase SignalingProtein Tyrosine Phosphatases

Cooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis

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Nogueira, C, Kim, K-H, Sung, H, Paraiso, K H T, Dannenberg, J-H, Bosenberg, M, Chin, L, Kim, M·2010·Oncogene

Abstract

Mitogen-activated protein kinase (MAPK) and AKT pathways are frequently co-activated in melanoma through overexpression of receptor tyrosine kinases, mutations in their signaling surrogates, such as RAS and BRAF, or loss of negative regulators such as PTEN. As RAS can be a positive upstream regulator of PI3-K, it has been proposed that the loss of PTEN and the activation of RAS are redundant events in melanoma pathogenesis. Here, in genetically engineered mouse models of cutaneous melanomas, we sought to better understand the genetic interactions between HRAS activation and PTEN inactivation in melanoma genesis and progression in vivo. We showed that HRAS activation cooperates with Pten+/- and Ink4a/Arf-/- to increase melanoma penetrance and promote metastasis. Correspondingly, gain- and loss-of-function studies established that Pten loss increases invasion and migration of melanoma cells and non-transformed melanocytes, and such biological activity correlates with a shift to phosphorylation of AKT2 isoform and E-cadherin down-regulation. Thus, Pten inactivation can drive the genesis and promote the metastatic progression of RAS activated Ink4a/Arf deficient melanomas.

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Crossref · 10.1038/onc.2010.349

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  • Interplay between the PI3K-AKT and KRAS-MAPK signaling cascades is known at multiple levels.

    “Various levels of interplay are known between the PI3K-AKT and KRAS-MAPK signaling cascades139, including for potential therapy.”
  • Network analysis connects oncogenic RAS to several mutated driver genes-KMT2D, PIK3CA, PTEN, and IDH1-that control signaling and metabolic pathways in KRAS-driven cancers.

    “Network analysis of the several driver mutation genes, including KMT2D138, PIK3CA139, PTEN140, and IDH1141, that regulate signaling and metabolic pathways in KRAS-driven cancers, connects them to oncogenic RAS (Fig 4c).”

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Authors
Nogueira, C., Kim, K.-H., Sung, H., Paraiso, K. H. T., Dannenberg, J.-H., Bosenberg, M., Chin, L., & Kim, M.
Affiliations
  • Dana-Farber Cancer Institute (US)
  • Moffitt Cancer Center (US)
  • University of Vermont (US)
  • Harvard University (US)
Corresponding author
  • Chin, L
  • Kim, M
Venue
Oncogene
Published
2010-08-16
Volume
29
Issue
47
Pages
6222-6232
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
OpenAlex
W2147690515
Cited by
108
References
75
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 10 · 2020: 2 · 2019: 3 · 2018: 6 · 2017: 7 · 2016: 8 · 2015: 6 · 2014: 4 · 2013: 15 · 2012: 14
FWCI
6.00
Type
journal article
Language
en
Open access
Locations
  • Oncogene (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA93947, R01CA093947, U01CA084313, UO1 CA84313)
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
melanoma, PTEN loss, Ras activation, HRAS, CDKN2A, Ink4a/Arf, melanoma metastasis, genetic interactions, PI3K/Akt signaling, E-cadherin, epithelial-mesenchymal transition, tumor cell migration and invasion, Akt2 phosphorylation, RNA interference
MeSH terms
Animals, Cell Transformation, Neoplastic, Enzyme Activation, Humans, Isoenzymes, Melanocytes, Melanoma, Neoplasm Invasiveness, Neoplasm Metastasis, Down-Regulation, Cadherins, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Gene Knockdown Techniques

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