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PTEN signaling pathways in melanoma

Oncogene volume 22, pages 3113–3122 (2003)Cite this article

Abstract

Phosphatase and tensin homolog deleted in from chromosome ten (PTEN), initially also known as mutated in multiple advanced cancers or TGF-β-regulated and epithelia cell-enriched phosphatase, is a tumor suppressor gene that is mutated in a large fraction of human melanomas. A broad variety of human cancers carry PTEN alterations, including glioblastomas, endometrial, breast, thyroid and prostate cancers. The PTEN protein has at least two biochemical functions: it has both lipid phosphatase and protein phosphatase activity. The lipid phosphatase activity of PTEN decreases intracellular PtdIns(3,4,5)P3 level and downstream Akt activity. Cell-cycle progression is arrested at G1/S, mediated at least partially through the upregulation of the cyclin-dependent kinase inhibitor p27. In addition, agonist-induced apoptosis is mediated by PTEN, through the upregulation of proapoptotic machinery involving caspases and BID, and the downregulation of antiapoptotic proteins such as Bcl2. The protein phosphatase activity of PTEN is apparently less central to its involvement in tumorigenesis. It is involved in the inhibition of focal adhesion formation, cell spreading and migration, as well as the inhibition of growth factor-stimulated MAPK signaling. Therefore, the combined effects of the loss of PTEN lipid and protein phosphatase activity may result in aberrant cell growth and escape from apoptosis, as well as abnormal cell spreading and migration. In melanoma, PTEN loss has been mostly observed as a late event, although a dose-dependent loss of PTEN protein and function has been implicated in early stages of tumorigenesis as well. In addition, loss of PTEN and oncogenic activation of RAS seem to occur in a reciprocal fashion, both of which could cooperate with CDKN2A loss in contribution to melanoma tumorigenesis.

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  1. Department of Hematology/Oncology, Massachusetts General Hospital, GRJ1021, 55 Fruit Street, Boston, 02114, USA, MA

    Heng Wu, Vikas Goel & Frank G Haluska

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Correspondence to Frank G Haluska.

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Wu, H., Goel, V. & Haluska, F. PTEN signaling pathways in melanoma. Oncogene 22, 3113–3122 (2003). https://doi.org/10.1038/sj.onc.1206451

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