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Biomap#37

Title: Akt / PI3K pathway
 
Legend: Akt (protein kinase B, PKB), a serine/threonine kinase, is a key regulator of cell survival and is clearly involved in the development of several human tumors, including melanoma. Increased Akt activity occurs in most sporadic metastatic melanomas. Of the three known isoforms (Akt1/PKB alpha, Akt2/PKB beta, Akt3/PKB gamma), Akt3 is the isoform most frequently elevated in melanoma. Akt inhibition causes apoptosis selectively in malignant cells expressing activated Akt, a minimal effect being observed in normal cells or tumor cells expressing low levels of activated Akt. Upstream of Akt is PI3K (phosphatidyl inositol 3-kinase) that is activated as a result of ligand-dependent activation of different types of receptors (e.g., receptor tyrosine kinases [RTK], G-protein coupled receptors [GPCR]): this occurs either directly (the PI3K/p85 regulatory subunit recognizes a phosphorylated tyrosine residue on the activated receptor through its SH2 [Src homology-2] domain) or indirectly (the PI3K/p110 catalytic subunit is activated by RAS following receptor dependent RAS activation). Receptor-independent activation can also occur, as in tumors (including melanoma) expressing constitutively active forms of RAS. Although no activating mutations or amplifications of Akt genes have been documented in melanomas, overexpression of the structurally normal Akt3 protein has been reported. A prominent mechanism leading to Akt activation in melanomas occurs as a result of decreased PTEN (phosphatase and tensin homolog) activity. PTEN is a phosphatase that negatively regulates Akt, its primary function being conversion of PIP3 (phosphatidyl inositol tris-phosphate) to PIP2. Combining mutational and epigenetic silencing studies suggests that PTEN might be involved in up to 60% of non-familial melanomas. REFERENCES: [1] Jiang BH, Biochim Biophys Acta 2007, 1784:150-8. [2] Hennessy BT, Nat Rev Drug Discov 2005, 4:988-1004. [3] Robertson GP, Cancer Metastasis Rev 2005, 24:273-85.
Author: The MMMP Team (updated: March 2009)

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