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- Title
Cooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis.
- Authors
Nogueira, C; Kim, K-H; Sung, H; Paraiso, K H T; Dannenberg, J-H; Bosenberg, M; Chin, L; Kim, M
- 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.
- Publication
Oncogene, 2010, Vol 29, Issue 47, p6222
- ISSN
1476-5594
- Publication type
Journal Article
- DOI
10.1038/onc.2010.349