PTEN, more than the AKT pathway

Abstract

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/phosphatidylinositol 3-kinase (PI3K)/AKT constitute an important pathway regulating the signaling of multiple biological processes such as apoptosis, metabolism, cell proliferation and cell growth. PTEN is a dual protein/lipid phosphatase and its main substrate phosphatidyl-inositol 3,4,5 triphosphate (PIP3) is the product of PI3K. Increase in PIP3 recruits AKT to the membrane where is activated by other kinases also dependent on PIP3. Many components of this pathway have been described as causal forces in cancer. PTEN activity is lost by mutations, deletions or promoter methylation silencing at high frequency in many primary and metastatic human cancers. Germ line mutations of PTEN are found in several familial cancer predisposition syndromes. Recently, many activating mutations in the PI3KCA gene (coding for the p110a catalytic subunit of PI3K) have been described in human tumors. Activation of PI3K and AKT are reported to occur in breast, ovarian, pancreatic, esophageal and other cancers. Genetically modified mice confirm these PTEN activities. Tissue-specific deletions of PTEN usually provoke cancer. Moreover, an absence of PTEN cooperates with an absence of p53 to promote cancer. However, we have observed very different results with the expression of activated versions of AKT in several tissues. Activated AKT transgenic lines do not develop tumors in breast or prostate tissues and do not cooperate with an absence of p53. This data suggest that an AKT-independent mechanism contributes to PTEN tumorigenesis. Crosses with transgenic mice expressing possible PTEN targets indicate that neither cyclin D1 nor p53 are these AKT-independent targets. However, AKT is more than a passive bridge toward PTEN tumorigenesis, since its expression not only allows but also enforces and accelerates the tumorigenic process in combination with other oncogenes. The PTEN/AKT pathwayPhosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a dual lipid and protein phosphatase. Its primary target is the PIP3 (1), the direct product of the phosphatidylinositol 3-kinase (PI3K). Loss of PTEN function, either in murine embryonic stem cells or in human cancer cell lines, results in accumulation of PIP3 mimicking the effect of PI3K activation and triggering the activation of its downstream effectors, PDK1, AKT/PKB and Rac1/cdc42. PDK1 contains a C-terminal pleckstrin homology domain, which binds the membrane-bound PIP3 triggering PDK1 activation. Activated PDK1 phosphorylates AKT at thr308 activating its serine-threonine kinase activity (100-fold over the basal). Once phosphorylated in T308, further activation occurs by PDK2 (the complex rictor-mTOR or DNA-PK) by phosphorylation at S473. AKT activation stimulates cell cycle progression, survival, metabolism and migration through phosphorylation of many physiological substrates (2-6). AKT is a serinethreonine kinase downstream of PTEN/PI3K that has three family members: AKT1, AKT2 and AKT3, which are encoded by three di...

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

“…Interestingly, prolonged stimulation of schwannoma cells with recombinant IGFBP-1 increases AKT activity ( Figure 6). As PTEN is an important AKT antagonist regulating cell growth (Blanco-Aparicio et al, 2007;Liu et al, 2008;Feron et al, 2009) (Perks et al, 2007), IGFBP-1 also contributes to the downregulation of PTEN (Figure 6). Thus, based on our data we here demonstrate a novel mechanism involved in schwannoma development via autocrine release of IGFBP-1, which downregulates PTEN leading to increased AKT activity and survival of schwannoma cells ( Figure 6).…”

The Role of Pea3 Group Transcription Factors in Esophageal Squamous Cell Carcinoma

“…PI3K-Akt pathway activity has been an important prognostic determinant of ESCC. [45][46][47] COX-2 inhibition reduces Akt phosphorylation in ovarian, prostate, and esophageal cancers, 48 -50 implying that COX-2 might be a key intermediate between Pea3 and Akt. However, COX-2 mRNA expression levels were not significantly different between EC109 shScr, shPea3-1, and shPea3-2 cells.…”

The role of early life genistein exposures in modifying breast cancer risk

“…Inactivating mutations or deletions of the PTEN gene are among the most common changes found in human cancers, particularly in prostate and endometrial cancers (Blanco-Aparicio et al, 2007). Downregulation in PTEN expression or signalling has also been identified in several other types of cancers, including inherited and sporadic breast cancers.…”