Membrane localization of all class I PI 3‐kinase isoforms suppresses c‐Myc‐induced apoptosis in Rat1 fibroblasts via Akt

Link, Wolfgang; Rosado, Aranzazú; Fominaya, Jesús; Thomas, James E.; Carnero, Amancio

doi:10.1002/jcb.20479

Cited by 33 publications

(25 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data also show quantitative differences in the amount of PIP3 (as measured indirectly by the relocation of GFP-Akt1) generated in yeast by p110a and p110h isoforms, which render distinct quantitative lack-of-growth phenotypes. This is consistent with the cell type-dependent distinct kinetic and oncogenic properties of p110a and p110h kinases (27)(28)(29). The comparison of the growth inhibition ( Fig.…”

Section: Resultssupporting

confidence: 85%

In vivo Functional Analysis of the Counterbalance of Hyperactive Phosphatidylinositol 3-Kinase p110 Catalytic Oncoproteins by the Tumor Suppressor PTEN

Andrés-Pons

Rodríguez-Escudero²,

Gil³

et al. 2007

Cancer Research

View full text Add to dashboard Cite

The signaling pathways involving class I phosphatidylinositol 3-kinases (PI3K) and the phosphatidylinositol-(3,4,5)-trisphosphate phosphatase PTEN regulate cell proliferation and survival. Thus, mutations in the corresponding genes are associated to a wide variety of human tumors. Heterologous expression of hyperactive forms of mammalian p110A and p110B in Saccharomyces cerevisiae leads to growth arrest, which is counterbalanced by coexpression of mammalian PTEN. Using this in vivo yeast-based system, we have done an extensive functional analysis of germ-line and somatic human PTEN mutations, as well as a directed mutational analysis of discrete PTEN functional domains. A distinctive penetrance of the PTEN rescue phenotype was observed depending on the levels of PTEN expression in yeast and on the combinations of the inactivating PTEN mutations and the activating p110A or p110B mutations analyzed, which may reflect pathologic differences found in tumors with distinct alterations at the p110 and PTEN genes or proteins. We also define the minimum length of the PTEN protein required for stability and function in vivo. In addition, a random mutagenesis screen on PTEN based on this system allowed both the reisolation of known clinically relevant PTEN mutants and the identification of novel PTEN loss-of-function mutations, which were validated in mammalian cells. Our results show that the PI3K/PTEN yeast-based system is a sensitive tool to test in vivo the pathologic properties and the functionality of mutations in the human p110 proto-oncogenes and the PTEN tumor suppressor and provide a framework for comprehensive functional studies of these tumor-related enzymes.

show abstract

Section: Resultssupporting

confidence: 85%

In vivo Functional Analysis of the Counterbalance of Hyperactive Phosphatidylinositol 3-Kinase p110 Catalytic Oncoproteins by the Tumor Suppressor PTEN

Andrés-Pons

Rodríguez-Escudero²,

Gil³

et al. 2007

Cancer Research

View full text Add to dashboard Cite

show abstract

“…AKT1 knockout (KO) cells lose the ability to compete with wild-type (WT) or PTEN-null cells (15). Similarly, inactivation of AKT by dominant-negative mutants inhibits the survival advantage provided by activated class I PI3K (16). These and other results point out the essential role of AKT in the PTEN/PI3K pathway (17)(18)(19)(20)(21).…”

Section: The Pten/akt Pathwaymentioning

confidence: 84%

PTEN, more than the AKT pathway

et al. 2007

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…However, adding a myristylation signal to the N terminus of p110␤ results in a constitutive, serum-independent activation of Akt (47,48). Similarly, the myristylated form of p110␥ also induces constitutive activation of Akt in Rat1 fibroblasts (48), but the stimulating effect of the wild-type p110␥ on Akt is revealed only in the presence of serum (Fig. 3B), and that effect is weak compared to that of the ␣ and ␦ isoforms.…”

Section: Discussionmentioning

confidence: 96%

“…These results are consistent with the recent findings showing that the wild-type p110␤ by itself does not induce activation of Akt in human mammary epithelial cells under serum-starved conditions (47). However, adding a myristylation signal to the N terminus of p110␤ results in a constitutive, serum-independent activation of Akt (47,48). Similarly, the myristylated form of p110␥ also induces constitutive activation of Akt in Rat1 fibroblasts (48), but the stimulating effect of the wild-type p110␥ on Akt is revealed only in the presence of serum (Fig.…”

Section: Discussionmentioning

confidence: 97%

Oncogenic transformation induced by the p110β, -γ, and -δ isoforms of class I phosphoinositide 3-kinase

Kang

Denley²,

Vanhaesebroeck³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

255

231

View full text Add to dashboard Cite

Class I phosphoinositide 3-kinase contains four isoforms of the catalytic subunit, p110␣, -␤, -␥, and -␦. At physiological levels of expression, the wild-type p110␣ isoform lacks oncogenic potential, but gain-of-function mutations and overexpression of p110␣ are correlated with oncogenicity. The p110␤, -␥, and -␦ isoforms induce transformation of cultured cells as wild-type proteins. This oncogenic potential requires kinase activity and can be suppressed by the target of rapamycin inhibitor rapamycin. The p110␦ isoform constitutively activates the Akt signaling pathway; p110␥ activates Akt only in the presence of serum. The isoforms differ in their requirements for upstream signaling. The transforming activity of the p110␥ isoform depends on rat sarcoma viral oncogene homolog (Ras) binding; preliminary data suggest the same for p110␤ and indicate Ras-independent oncogenic potential of p110␦. The surprising oncogenic potential of the wild-type non-␣ isoforms of class I phosphoinositide 3-kinase may explain the dearth of cancerspecific mutations in these proteins, because these non-␣ isoforms could contribute to the oncogenic phenotype of the cell by differential expression.Akt

show abstract

Membrane localization of all class I PI 3‐kinase isoforms suppresses c‐Myc‐induced apoptosis in Rat1 fibroblasts via Akt

Cited by 33 publications

References 30 publications

In vivo Functional Analysis of the Counterbalance of Hyperactive Phosphatidylinositol 3-Kinase p110 Catalytic Oncoproteins by the Tumor Suppressor PTEN

In vivo Functional Analysis of the Counterbalance of Hyperactive Phosphatidylinositol 3-Kinase p110 Catalytic Oncoproteins by the Tumor Suppressor PTEN

PTEN, more than the AKT pathway

Oncogenic transformation induced by the p110β, -γ, and -δ isoforms of class I phosphoinositide 3-kinase

Contact Info

Product

Resources

About