Cooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis
Open accessAbstract
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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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.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [139]
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).”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [139]
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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
- PMC
- PMC2989338
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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